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PubMed2006

Genetic evaluation of somatic cell score in dairy cattle considering first and later lactations as two different but correlated traits.

A test-day (TD) random regression model (RRM) was described for the genetic evaluation of somatic cell score (SCS) where first and later lactations were considered as two different but correlated traits. A two-step covariance function procedure was used to estimate variance-covariances and associated genetic parameters. Analysis of estimated breeding values (EBV), ranking of top bulls and cows and some computational aspects were used to compare RRM with TD repeatability model (RPM) and lactation average model (LAM). Residuals were analysed to assess the relative fit of TD models. Comparison between RRM and RPM showed that RRM has lower mean squared error and gave better fit to the data. For young bulls and cows, the standard deviation (SD) of EBVs was highest for RRM and lowest for LAM implying efficient utilization of information on SCS, in terms of revealing more genetic variation. A much lower correlation of EBVs ranging from 0.80 to 0.92 and significant re-ranking of top bulls and cows were observed between RRM and LAM. The lower across-lactation correlation between RRM and LAM indicated that LAM is directed to give more weight to first lactation breeding values. The RRM, where SCS in the first and later lactations was considered as two different but correlated traits was able to make effective use of available information on young bulls and cows, and could offer an opportunity to breeders to utilize EBVs for first and later lactations.

Animals↗
PubMed1995

Hemodynamic and microcirculatory changes during development of renal hypertension.

To study the progression of vessel loss (rarefaction) during the development of hypertension, a plastic window was chronically implanted over the biceps femoralis muscle of reduced renal mass (RRM) and sham-operated control (SOC) rats on a low-salt diet (0.4%). Blood pressure was measured directly via a catheter implanted in the femoral artery, and tissue blood flow was measured by laser-Doppler flowmetry before and after local topical application of sodium nitroprusside. Measurements were made on the control day and after an increase in sodium intake (4.0%) in RRM rats on days 5, 10, 14, 21, and 28. SOC rats on a low-salt diet served as the control group. RRM rats became hypertensive (167 mmHg), and vascular resistance increased after a change in sodium intake. Resting tissue blood flow decreased by 19% by day 28 in RRM but did not change in SOC. Sodium nitroprusside administration reduced vascular resistance to the same level in both RRM and SOC during control and at day 10; however, on all other days, sodium nitroprusside was not able to fully dilate the RRM microcirculation compared with that of SOC. At the same time, microvascular density estimated by computer fluorescence microscopy was decreased by 25% in RRM rats. These studies indicate that the development of RRM hypertension is characterized by a transition from increased tone and vessel closure (functional rarefaction) to anatomic vessel loss (structural rarefaction).

Analysis of Variance↗
PubMed2005

The N- and C-terminal RNA recognition motifs of splicing factor Prp24 have distinct functions in U6 RNA binding.

Prp24 is an essential yeast U6 snRNP protein with four RNA recognition motifs (RRMs) that facilitates the association of U4 and U6 snRNPs during spliceosome assembly. Genetic interactions led to the proposal that RRMs 2 and 3 of Prp24 bind U6 RNA, while RRMs 1 and 4 bind U4 RNA. However, the function of each RRM has yet to be established through biochemical means. We compared the binding of recombinant full-length Prp24 and truncated forms lacking RRM 1 or RRM 4 with U6 RNA. Contrary to expectations, we found that the N-terminal segment containing RRM 1 is important for high-affinity binding to U6 RNA and for discrimination between wild-type U6 RNA and U6 with point mutations in the 3' intramolecular stem-loop. In contrast, deletion of RRM 4 and the C terminus did not significantly alter the affinity for U6 RNA, but resulted in the formation of higher order Prp24.U6 complexes. Truncation and internal deletion of U6 RNA mapped three Prp24-binding sites, with the central site providing most of the affinity for Prp24. A newly identified temperature-sensitive lethal point mutation in RRM 1 is exacerbated by mutations in the U6 RNA telestem, as is a mutation in RRM 2, but not one in RRM 3. We propose that RRMs 1 and 2 of yeast Prp24 bind the same central site in U6 RNA that is bound by the two RRMs of human Prp24, and that RRMs 3 and 4 bind lower affinity flanking sites, thereby restricting the stoichiometry of Prp24 binding.

Amino Acid Sequence↗
PubMed1983

The pharmacokinetics of metformin: a comparison of the properties of a rapid-release and a sustained-release preparation.

The pharmacokinetic differences between a rapid-release metformin preparation of 500 mg (RRM) and a sustained-release metformin preparation of 500 mg (SRM), whose gastrointestinal side effects may be less, were compared after a single dose and after continuous 5-day use during a steady-state phase. In the single-dose trial the mean peak serum level of 1.00 micrograms/ml from RRM and 0.61 micrograms/ml from SRM were reached at 3 h, and at 3 and 4 h, respectively, after ingestion of the drugs. Serum metformin levels from RRM were consistently higher up to 8 h, and the AUC0-8h value for RRM was from 4.25 and 2.49 for SRM (p less than 0.001). Over a 24-h period 40% of the given dose was recovered in urine from RRM. The value for SRM was 25%. The elimination half-life was 2.0 h for RRM and 2.6 h for SRM. During the steady-state trial the mean basal serum metformin concentration was higher after SRM (0.33 micrograms/ml) than after RRM (0.20 micrograms/ml), although the mean peak serum metformin level remained lower after SRM. On the 5th day the AUC0-8h values obtained after RRM and SRM were comparable (6.88 vs 6.59; N.S.).

Adult↗
PubMed1996

Individual RNA recognition motifs of TIA-1 and TIAR have different RNA binding specificities.

TIA-1 and TIAR are two closely related RNA recognition motif (RRM) proteins which possess three RRM-type RNA binding domains (RRMs 1, 2, and 3). Although both proteins have been implicated as effectors of apoptotic cell death, the specific functions of TIA-1 and TIAR are not known. We have performed in vitro selection/amplification from pools of random RNA sequences to identify RNAs to which TIA-1 and TIAR bind with high affinity. Both proteins selected RNAs containing one or several short stretches of uridylate residues suggesting that the two proteins have similar RNA binding specificities. Replacement of the uridylate stretch with an equal number of cytidine residues eliminates the protein-RNA interaction. Mutational analysis indicates that, for both TIA-1 and TIAR, it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs. Although RRM 2 is both necessary and sufficient for this interaction, the affinity for the selected RNA (as determined by filter binding assays) does increase when the second domain of TIAR is expressed together with the first and third domains (Kd = 2 x 10(-8) M) rather than alone (Kd = 5 x 10(-8) M). Although RRM 3 (of either TIA-1 or TIAR) does not interact with the uridylate-rich sequences selected by the full-length proteins, it is a bona fide RNA binding domain capable of affinity-precipitating a population of cellular RNAs ranging in size from 0.5 to 5 kilobases. In contrast, RRM 1 does not affinity-precipitate cellular RNA. The inability of RRM 1 to interact with RNA may be due to the presence of negatively charged amino acids within the RNP 1 octamer.

Base Sequence↗
PubMed1988

Endogenous noradrenaline re-uptake blocking factor in rats with reduced renal mass hypertension.

This study was carried out to elucidate the involvement of the peripheral sympathetic nervous system in the pathogenesis of reduced renal mass (RRM)-salt hypertension in rats. Male Wistar rats underwent subtotal nephrectomy (70-80% reduction in renal mass). On the 10th postoperative day, systolic blood pressure was higher in RRM-salt rats than in RRM-water rats. Perfusion of isolated mesenteric vasculature from normotensive rats, with the deproteinized plasma from RRM-salt hypertensive rats induced significantly higher pressor responses and noradrenaline overflow with electrical stimulation than the perfusate from RRM-water normotensive rats; the responses to exogenous noradrenaline showed no significant changes. In the presence of desipramine, noradrenaline overflow did not increase following perfusion with plasma from RRM-salt hypertensive rats. These data indicate that plasma from rats with RRM-salt hypertension might contain some noradrenaline re-uptake blocking factor.

Animals↗
PubMed2000

Exposure to high concentrations of nitrosamines and cancer mortality among a cohort of rubber workers.

OBJECTIVES: To examine if the occurrence of different cancers was increased among rubber workers, as the highest known exposures of humans to nitrosamines have occurred in the rubber industry. METHODS: A cohort of 8933 rubber workers (hired after 1 January 1950, still active or retired on 1 January 1981 and employed for at least 1 year in one of five study factories) was followed up for mortality from 1 January 1981 to 31 December 1991. Work histories were reconstructed with routinely documented cost centre codes, which allowed identification by employment in specific work areas. For each cost centre code time and factory specific, semi-quantitative exposures to nitrosamines (three levels: low, medium, high) and other compounds were estimated by industrial hygienists. Rate ratios for medium (RRm) and high (RRh) exposures and 95% confidence intervals (95% CIs) were calculated with Cox's proportional hazards models with the low exposure as reference. RESULTS: Exposure to nitrosamines was significantly associated with an increased mortality from cancers of the oesophagus (13 deaths: RRm 1.7, 95% CI 0.3 to 10.3; RRh 7.3, 95% CI 1.9 to 27.8) and of the oral cavity and pharynx (17 deaths: RRm 0.8, 95% CI 0.2 to 4.1; RRh 3.9, 95% CI 1.4 to 11.1). A non-significant trend of increasing mortality with exposure to higher concentrations of nitrosamines was found for mortality from cancer of the prostate (26 deaths: RRm 1.4, 95% CI 0.5 to 3.8; RRh 2.2, 95% CI 0.9 to 5.6), and the brain (six deaths: RRm 3.9, 95% CI 0.3 to 42.6; RRh 6.0, 95% CI 0.6 to 57.6). No association was found between exposure to nitrosamines and cancer of the stomach (RRm 0.8, 95% CI 0.4 to 1.8; RRh 1.2, 95% CI 0.5 to 2.5) or lung (RRm 1.0, 95% CI 0.6 to 1.5; RRh 1.0, 95% CI 0.7 to 1.6). CONCLUSIONS: Exposure to high concentrations of nitrosamines is associated with increased mortality from cancers of the oesophagus, oral cavity, and pharynx, but not with increased mortality from cancers of the stomach or lung.

Adult↗
PubMed2000

Microvascular flow and tissue PO(2) in skeletal muscle of chronic reduced renal mass hypertensive rats.

This study determined whether arteriolar blood flow, capillary red blood cell (RBC) velocity, capillary hematocrit (Hct(cap)), and tissue PO(2) are altered in cremaster muscles of rats with chronic reduced renal mass hypertension (RRM-HT) relative to normotensive rats on high- or low-salt (NT-HS vs. NT-LS) diet. The blood flow in first- through third-order arterioles was not different between NT and HT rats, either at rest or during maximal relaxation of the vessels with 10(-4) M adenosine. Capillary RBC velocity was similar between the groups at rest but was elevated in RRM-HT and NT-HS rats during adenosine superfusion. Hct(cap) was reduced at rest in RRM-HT and NT-HS rats compared with NT-LS and was reduced in RRM-HT rats during adenosine-induced dilation. Tissue PO(2) was reduced in RRM-HT and NT-HS rats compared with NT-LS rats during control conditions and was lower in RRM-HT than in NT-LS rats during adenosine-induced dilation. These results indicate that both RRM-HT and chronic exposure of normotensive rats to a high-salt diet lead to reduced tissue oxygenation, despite the maintenance of normal arteriolar blood flow.

Adenosine↗
PubMed1996

Rapid microvessel rarefaction with elevated salt intake and reduced renal mass hypertension in rats.

To identify the sequence of events associated with the development of reduced vessel density (rarefaction) in hypertension, microvessel density and ultrastructure were assessed in the cremaster muscle of rats subjected to a 75% surgical reduction of renal mass and normotensive sham-operated control rats. Rats with reduced renal mass (RRM rats) and sham-operated rats were then maintained on either a high salt (4.0% NaCl) or a low salt (0.4% NaCl) diet for 3 days. Acute exposure to the high salt diet significantly increased mean arterial pressure in RRM rats but did not affect sham-operated control rats. Quantitative fluorescence microscopy of cremaster muscle whole mounts using rhodamine-labeled Griffonia simplicifolia I lectin revealed substantial rarefaction of microvessels in both RRM hypertensive rats and normotensive sham-operated rats on a high salt diet relative to corresponding control rats on a low salt diet. Confocal microscopy revealed a heterogeneous distribution of microvessels in RRM rats on a high salt diet, with some areas largely devoid of vessels. RRM and sham-operated rats on a high salt diet both exhibited changes in arteriolar ultrastructure, which included a loss of basement membranes and a dissociation of the endothelial and smooth muscle components of the vascular wall, resulting in a loss of vessel integrity. These observations demonstrate that a rapid loss of microvessels can occur not only in rats with RRM hypertension but also in normotensive rats on a high salt diet. This loss of microvessels results from structural alterations, which differ from the degenerative processes associated with microvascular rarefaction in rats with chronic RRM hypertension.

Animals↗
PubMed1997

A novel zinc finger-containing RNA-binding protein conserved from fruitflies to humans.

The Drosophila lark gene encodes an essential RNA-binding protein of the RNA recognition motif (RRM) class that is required during embryonic development. Genetic analysis demonstrates that it also functions as a molecular element of a circadian clock output pathway, mediating the temporal regulation of adult emergence in the fruitfly. We now report the molecular characterization of a human gene with significant similarity to lark. Based on fluorescence in situ hybridization and radiation hybrid mapping, the human gene has been localized to chromosome region 11q13; it is closely linked to several identified genes including the locus of Bardet-Biedl syndrome type 1. The lark-homologous human gene expresses a single 1.8-kb size class of mRNA in most or all tissues including brain. Additional database searches have identified a mouse counterpart that is virtually identical to the human protein. Similar to lark protein, both mammalian proteins contain two copies of the RRM-type consensus RNA-binding motif. Unlike most RRM family members, however, the Drosophila and mammalian proteins also contain a retroviral-type (RT) zinc finger that is situated 43 residues C-terminal to the second RRM element. Within a 184-residue segment spanning the RRM elements and the RT zinc finger, the human and mouse proteins are 61% similar to the Drosophila lark sequence. These common sequence features and comparisons among a large collection of RRM proteins suggest that the human and mouse proteins represent homologues of Drosophila lark.

Adult↗
PubMed1999

Acute elevations in salt intake and reduced renal mass hypertension compromise arteriolar dilation in rat cremaster muscle.

Alterations in arteriolar reactivity to dilator agonists were assessed in the skeletal muscle microcirculation of normotensive male Sprague-Dawley rats fed either high- (4% NaCl; HS) or low- (0. 4% NaCl; LS) salt diets and in reduced renal mass hypertensive rats (RRM-HT) on a high-salt diet for 3 days. An in situ cremaster muscle preparation was superfused with physiological salt solution, transilluminated, and viewed via television microscopy. A videomicrometer was used to measure changes in diameter of distal arterioles in response to increasing concentrations of acetylcholine (ACH), iloprost (ILO), cholera toxin (CT), forskolin (FOR), and sodium nitroprusside (SNP). Arteriolar dilation in response to ACH, ILO, and CT was significantly reduced in both HS and RRM-HT rats, while responses to FOR and SNP were decreased in RRM-HT rats only. The maximum dilation of the arterioles (determined during superfusion of the muscle with Ca2+-free solution containing 10(-4) M adenosine) was similar in the normotensive control animals on LS and HS diets, but was reduced in the RRM-HT rats, suggesting that early anatomic remodeling of the vessel wall may be occurring with RRM-HT. We conclude that arteriolar reactivity to endothelium-dependent and -independent vasodilator agonists is impaired as early as 3 days after the development of RRM hypertension or commencement of a high-salt diet in normotensive rats. Structural remodeling of the arteriolar wall, although becoming evident in the hypertensive rats, takes longer to develop than the impaired vasodilator reactivity.

Animals↗
PubMed2000

Reduced renal mass hypertension, but not high salt diet, alters skeletal muscle arteriolar distensibility and myogenic responses.

The effects of high salt diet and reduced renal mass hypertension (RRM-HT) on skeletal muscle arteriolar distensibility and myogenic responses were investigated in male Sprague-Dawley rats. Rats were enclosed in an air-tight box with the in situ cremaster muscle exteriorized and viewed via television microscopy. Normotensive rats were fed low salt (0.4% NaCl) or high salt (4.0% NaCl) diet and RRM-HT rats were fed high salt diet for 4-6 weeks. With the cremaster muscle superfused with either physiological salt solution (for myogenic responses) or Ca(2+)-free physiological salt solution (for arteriolar distensibility), box pressure (and therefore, intravascular pressure) was increased in 5 mm Hg increments to a maximum of +30 mm Hg. The myogenic responses of arterioles were not altered by high salt diet, but were enhanced with RRM-HT. Arteriolar distensibility was not affected by high salt diet, but was reduced in RRM-HT rats compared to either normotensive rat group. These data suggest that high salt diet does not significantly alter either myogenic responses or the distensibility of rat cremasteric arterioles. However, RRM-HT enhances myogenic responses of these vessels while reducing arteriolar distensibility. The impact of these effects must be taken into account when interpreting data describing alterations in skeletal muscle microvessel reactivity for animals on high salt diet or with RRM hypertension.

Adenosine↗
PubMed2003

Predictive factors in locally advanced rectal cancer treated with preoperative hyperfractionated and accelerated radiotherapy.

This study examines the prognostic significance of pathologic factors in patients with primary locally advanced rectal cancer treated prospectively with preoperative radiotherapy. From 1992 to 1998, 104 patients with rectal cancer of grades T3 or T4 and any N underwent preoperative radiotherapy followed by surgical resection. Survival curves were estimated according to the Kaplan-Meier method. Correlation of outcome with clinicopathologic variables (pathologic tumor and lymph node staging, histology, radial resection margin [RRM], clearance, vessel involvement, and tumor regression grade [TRG], quantitated in 5 grades) was evaluated using the Cox proportional hazards model. None of the patients achieved a histologically confirmed complete pathologic response, but 79% of the patients showed partial tumor regression (TRG2-4) and 21% did not show any tumor regression (TRG5). Among the tumors, 22% were of a mucinous type. The RRM was free of tumor in 76% of the surgical specimens. The median clearance was 2 mm. Vascular invasion was present in 37 cases (36%). In the univariate analysis, lymph node metastases, absence of tumor regression, positive RRM, and vascular invasion were correlated with adverse overall survival and disease-free survival; absence of tumor regression, positive RRM, and clearance <2 mm were correlated with local recurrences; and advanced pT stage was correlated only with disease-free survival. However, in the multivariate analysis, only lymph node metastases and RRM were independent prognostic factors for overall survival and disease-free survival, and clearance <2 mm was an independent prognostic factor for local control. Pathologic parameters remain strong determinants of local recurrence and survival in locally advanced rectal cancer, treated preoperatively with hyperfractionated and accelerated radiotherapy. We show that patients with advanced pT, positive lymph nodes, vascular invasion, positive RRM, clearance <2 mm, or absence of tumor regression are known to have poor clinical outcome.

Adult↗
PubMed1999

Effects of digoxin-specific antibody Fab fragment (Digibind) on blood pressure and renal water-sodium metabolism in 5/6 reduced renal mass hypertensive rats.

The importance of increased endogenous digitalis-like factor (EDLF) in volume-expanded hypertension has been generally agreed. To further clarify the role of EDLF on the development of hypertension and renal water-sodium handling in 5/6 reduced renal mass hypertensive rats (RRM), we studied the effects of acute administration of digoxin-specific antibody Fab fragment (Digibind) in the early phase and the chronic phase of hypertension in RRM. RRM and sham-operated rats were given 1% saline for 1 or 4 weeks. RRM were injected Digibind (60 mg/kg) or vehicle (0.9% saline) intravenously in the first or fourth week under thiobutabarbital anesthesia. All sham-operated rats were administered Digibind under the same condition. Digibind altered neither blood pressure, heart rate, urine volume, nor urinary sodium excretion in sham-operated rats. However, Digibind produced a gradual but significant decline in mean arterial pressure to the level slightly above that in sham-operated rats from 153 +/- 5 to 131 +/- 5 mm Hg in the first week and from 181 +/- 6 to 129 +/- 4 mm Hg in the fourth week without any significant change in heart rate. The decrease in mean arterial pressure at 160 min after Digibind administration in the fourth week (-48 +/- 5 mm Hg) was greater than that in the first week (-22 +/- 4 mm Hg). No differences were observed in urine volume, urinary sodium excretion, or plasma norepinephrine concentration between Digibind and vehicle-treated RRM in either week. These data suggest that EDLF would contribute to both the early and chronic phase in the development of hypertension in RRM.

Animals↗
PubMed2003

Solution structure and RNA interactions of the RNA recognition motif from eukaryotic translation initiation factor 4B.

Eukaryotic initiation factor 4B (eIF4B) is a multidomain protein with a range of activities that serves primarily to promote association of messenger RNA to the 40S ribosomal subunit during translation initiation. We report here the solution structure of the eIF4B RNA recognition motif (RRM) domain. It adopts a classical RRM fold, with a beta alpha beta beta alpha beta topology. The most striking difference with other RRM structures is in the disposition of loop 3, which connects the beta 2 and beta 3 strands and is implicated in RNA recognition. This loop folds down against the body of the RRM and exhibits restricted motion on a milli- to microsecond time scale. Although it contributes to a large basic patch on the RNA binding surface, it does not protrude out from the domain as observed in other RRM structures, possibly implying a different mode of RNA binding. On its own, the core RRM domain provides only a relative weak interaction with RNA targets and appears to require extensions at the N- and C-terminus for high-affinity binding.

Amino Acid Motifs↗
PubMed2006

Molecular recognition of an RNA trafficking element by heterogeneous nuclear ribonucleoprotein A2.

Heterogeneous nuclear ribonucleoprotein (hnRNP) A2 is a multitasking protein involved in RNA packaging, alternative splicing of pre-mRNA, telomere maintenance, cytoplasmic RNA trafficking, and translation. It binds short segments of single-stranded nucleic acids, including the A2RE11 RNA element that is necessary and sufficient for cytoplasmic transport of a subset of mRNAs in oligodendrocytes and neurons. We have explored the structures of hnRNP A2, its RNA recognition motifs (RRMs) and Gly-rich module, and the RRM complexes with A2RE11. Circular dichroism spectroscopy showed that the secondary structure of the first 189 residues of hnRNP A2 parallels that of the tandem betaalpha betabeta alphabeta RRMs of its paralogue, hnRNP A1, previously deduced from X-ray diffraction studies. The unusual GRD was shown to have substantial beta-sheet and beta-turn structure. Sedimentation equilibrium and circular dichroism results were consistent with the tandem RRM region being monomeric and supported earlier evidence for the binding of two A2RE11 oligoribonucleotides to this domain, in contrast to the protein dimer formed by the complex of hnRNP A1 with the telomeric ssDNA repeat. A three-dimensional structure for the N-terminal, two-RRM-containing segment of hnRNP A2 was derived by homology modeling. This structure was used to derive a model for the complex with A2RE11 using the previously described interaction of pairs of stacked nucleotides with aromatic residues on the RRM beta-sheet platforms, conserved in other RRM-RNA complexes, together with biochemical data and molecular dynamics-based observations of inter-RRM mobility.

Amino Acid Sequence↗
PubMed1994

RNP1, a new ribonucleoprotein gene of the yeast Saccharomyces cerevisiae.

A previously unidentified ribonucleoprotein (RNP) gene of yeast has been cloned and sequenced. The gene, named RNP1, was found adjacent to a previously sequenced gene encoding the second gene for ribosomal protein L4. RNP1 contains two RNA Recognition Motifs (RRM), [alternatively known as RNA binding Domains (RBD)], but unlike most RNP genes does not contain any auxiliary simple sequence domains. The first RRM (RRM1) most resembles RRM domains found in the hnRNP A/B class of RNP proteins. The second RRM (RRM2) most resembles a RRM so far seen only in the single RRM of the yeast SSB1 gene. Two null mutants of RNP1 that were created, a frameshift disruption and a complete deletion of the gene, were viable, demonstrating that the gene is not essential for cell growth. Two double null mutants of yeast RNP genes that were created (delta RNP1/delta SSB1 and delta SSB1/delta NPL3) were also viable. A fragment identical in size to the RRM1 domain could be amplified by PCR from the DNA of fungi, plants, and animals, using primers matching the ends of this domain, indicating that the structure of RRM1 is conserved. Another potential open reading frame on the same cloned fragment of DNA encodes a gene product whose structure resembles that of a seven-transmembrane-segment membrane receptor protein.

Amino Acid Sequence↗
PubMed2002

Correlated alternative side chain conformations in the RNA-recognition motif of heterogeneous nuclear ribonucleoprotein A1.

The RNA-recognition motif (RRM) is a common and evolutionarily conserved RNA-binding module. Crystallographic and solution structural studies have shown that RRMs adopt a compact alpha/beta structure, in which four antiparallel beta-strands form the major RNA-binding surface. Conserved aromatic residues in the RRM are located on the surface of the beta-sheet and are important for RNA binding. To further our understanding of the structural basis of RRM-nucleic acid interaction, we carried out a high resolution analysis of UP1, the N-terminal, two-RRM domain of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), whose structure was previously solved at 1.75-1.9 A resolution. The two RRMs of hnRNP A1 are closely related but have distinct functions in regulating alternative pre-mRNA splice site selection. Our present 1.1 A resolution crystal structure reveals that two conserved solvent-exposed phenylalanines in the first RRM have alternative side chain conformations. These conformations are spatially correlated, as the individual amino acids cannot adopt each of the observed conformations independently. These phenylalanines are critical for nucleic acid binding and the observed alternative side chain conformations may serve as a mechanism for regulating nucleic acid binding by RRM-containing proteins.

Amino Acids↗