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Martin Latterich

Publications and source records attributed to Martin Latterich.

10 recordsLinked to original sources
PubMed2006

p97: The cell's molecular purgatory?

The multifunctional AAA-ATPase p97/VCP is one of the most extensively studied members of this protein family, yet it presents the field with many perplexing questions surrounding its mechanism of substrate engagement and processing. Recent discoveries have unmasked a new purgatorial identity for this molecule in the ubiquitin-proteasome pathway, specifically its role in linking ubiquitylated substrates with competing ubiquitin conjugation and deconjugation machineries. Furthermore, biochemical studies surprisingly identify the C-terminal D2 ring as essential for substrate interaction, thus bringing p97 one step closer to its prokaryotic AAA protease relatives.

Adenosine Triphosphatases↗
PubMed2006

Publishing proteomic data.

Scientific publications should provide sufficient detail in terms of methodology and presented data to enable the community to reproduce the methodology to generate similar data and arrive at the same conclusion, if an identical sample is provided for analysis. The advent of high-throughput methods in biological experimentation impose some unique challenges both in data presentation in classical print format, as well as in describing methodology and data analysis in sufficient detail to conform to good publication practice. To facilitate this process, Proteome Science is adopting a set of methodology and data presentation guidelines to enable both peer reviewers, as well as the scientific community, to better evaluate high-throughput proteomic studies.

Editorial↗
PubMed2006

p97 adaptor choice regulates organelle biogenesis.

The AAA protein p97 requires adaptor-like cofactors for its numerous cellular functions. In this issue of Developmental Cell, Uchiyama et al. (2006) identify p37 as a p97 adaptor that is required constitutively for ER and Golgi membrane fusion, analogous to the mitotic membrane fusion role of the adaptor p47. Their study suggests that related p97 adaptors involved in similar cellular pathways can be subject to differential regulation.

Adenosine Triphosphatases↗
PubMed2005

Molecular systems biology at the crossroads: to know less about more, or to know more about less?

Systems biology is a rapidly evolving discipline that endeavours to understand the detailed coordinated workings of entire organisms, with the ultimate goal to detect differences between health and disease, or to understand how cells or entire organisms react to the environment. The editorial provides a critical evaluation of what molecular systems analysis can and cannot accomplish with existing methodologies, and how systems biology needs to merge with reductionism to yield a more comprehensive and mechanistically insightful model of a cell or organism.

Editorial↗
PubMed2004

Uncoupling retro-translocation and degradation in the ER-associated degradation of a soluble protein.

Aberrant polypeptides in the endoplasmic reticulum (ER) are retro-translocated to the cytoplasm and degraded by the 26S proteasome via ER-associated degradation (ERAD). To begin to resolve the requirements for the retro-translocation and degradation steps during ERAD, a cell-free assay was used to investigate the contributions of specific factors in the yeast cytosol and in ER-derived microsomes during the ERAD of a model, soluble polypeptide. As ERAD was unaffected when cytoplasmic chaperone activity was compromised, we asked whether proteasomes on their own supported both export and degradation in this system. Proficient ERAD was observed if wild-type cytosol was substituted with either purified yeast or mammalian proteasomes. Moreover, addition of only the 19S cap of the proteasome catalyzed ATP-dependent export of the polypeptide substrate, which was degraded upon subsequent addition of the 20S particle.

Animals↗
PubMed2004

Two methods of whole-genome amplification enable accurate genotyping across a 2320-SNP linkage panel.

Comprehensive genome scans involving many thousands of SNP assays will require significant amounts of genomic DNA from each sample. We report two successful methods for amplifying whole-genomic DNA prior to SNP analysis, multiple displacement amplification, and OmniPlex technology. We determined the coverage of amplification by analyzing a SNP linkage marker set that contained 2320 SNP markers spread across the genome at an average distance of 2.5 cM. We observed a concordance of >99.8% in genotyping results from genomic DNA and amplified DNA, strongly indicating the ability of both methods used to amplify genomic DNA in a highly representative manner. Furthermore, we were able to achieve a SNP call rate of >98% in both genomic and amplified DNA. The combination of whole-genome amplification and comprehensive SNP linkage analysis offers new opportunities for genetic analysis in clinical trials, disease association studies, and archiving of DNA samples.

DNA↗
PubMed2003

DNA damage modulates nucleolar interaction of the Werner protein with the AAA ATPase p97/VCP.

We report a novel nucleolar interaction between the AAA ATPase p97/VCP and the Werner protein (WRNp), a member of the RecQ helicase family. p97/VCP mediates several important cellular functions in eucaryotic cells, including membrane fusion of the endoplasmic reticulum and Golgi and ubiquitin-dependent protein degradation. Mutations in the WRN gene cause Werner syndrome, a genetic disorder characterized by premature onset of aging symptoms, a higher incidence of cancer, and a high susceptibility to DNA damage caused by topoisomerase inhibitors. We observed that both WRNp and valosin-containing protein (VCP) were present in the nucleoplasm and in nucleolar foci in mammalian cells and that WRNp and p97/VCP physically interacted in the nucleoli. Importantly, the nucleolar WRNp/VCP complex was dissociated by treatment with camptothecin, an inhibitor of topoisomerase I, whereas other WRNp-associated protein complexes, such as WRNp/Ku 80, were not dissociated by this drug. Because WRN syndrome cells are sensitive to topoisomerase inhibitors, these observations suggest that the VCP/WRNp interaction plays an important role in WRN biology. We propose a novel role for VCP in the DNA damage response pathway through modulation of WRNp availability.

Adenosine Triphosphatases↗
PubMed2002

Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane.

Bcl-2 family proteins regulate the release of proteins like cytochrome c from mitochondria during apoptosis. We used cell-free systems and ultimately a vesicular reconstitution from defined molecules to show that outer membrane permeabilization by Bcl-2 family proteins requires neither the mitochondrial matrix, the inner membrane, nor other proteins. Bid, or its BH3-domain peptide, activated monomeric Bax to produce membrane openings that allowed the passage of very large (2 megadalton) dextran molecules, explaining the translocation of large mitochondrial proteins during apoptosis. This process required cardiolipin and was inhibited by antiapoptotic Bcl-x(L). We conclude that mitochondrial protein release in apoptosis can be mediated by supramolecular openings in the outer mitochondrial membrane, promoted by BH3/Bax/lipid interaction and directly inhibited by Bcl-x(L).

Animals↗
PubMedDate not supplied

Werner syndrome protein directly binds to the AAA ATPase p97/VCP in an ATP-dependent fashion.

We have previously shown that the Werner syndrome helicase, WRNp, a member of the RecQ helicase family, forms a tight molecular complex with the p97/Valosin containing protein (VCP), a member of the AAA (ATPases associated with diverse cellular activities) family of proteins. This interaction is disrupted by chemical agents that confer DNA damage, suggesting that VCP plays an important role in the signal-dependent release of WRNp from its nucleolar sequestration site. Here, we characterized the structural requirements for interactions between WRNp and VCP and for the nuclear localization of VCP. We discovered that VCP directly binds to the RQC (RecQ conserved) domain of WRNp, which is a highly conserved motif common to the RecQ helicase family. This interaction is ATP-dependent, suggesting that VCP plays a mechanistic role in releasing WRNp from the nucleolus. Immunohistochemical analysis of various VCP domains and mutated proteins expressed in vitro demonstrated that VCP may contain several hierarchical cellular localization motifs within its domain structure.

Active Transport, Cell Nucleus↗