title: Longin-like folds identified in CHiPS and DUF254 proteins: vesicle trafficking complexes conserved in eukaryotic evolution.
abstract: Eukaryotic protein trafficking pathways require specific transfer of cargo vesicles to different target organelles. A number of vesicle trafficking and membrane fusion components participate in this process, including various tethering factor complexes that interact with small GTPases prior to SNARE-mediated vesicle fusion. In Saccharomyces cerevisiae a protein complex of Mon1 and Ccz1 functions with the small GTPase Ypt7 to mediate vesicle trafficking to the vacuole. Mon1 belongs to DUF254 found in a diverse range of eukaryotic genomes, while Ccz1 includes a CHiPS domain that is also present in a known human protein trafficking disorder gene (HPS-4). The present work identifies the CHiPS domain and a sequence region from another trafficking disorder gene (HPS-1) as homologs of an N-terminal domain from DUF254. This link establishes the evolutionary conservation of a protein complex (HPS-1/HPS-4) that functions similarly to Mon1/Ccz1 in vesicle trafficking to lysosome-related organelles of diverse eukaryotic species. Furthermore, the newly identified DUF254 domain is a distant homolog of the mu-adaptin longin domain found in clathrin adapter protein (AP) complexes of known structure that function to localize cargo protein to specific organelles. In support of this fold assignment, known longin domains such as the AP complex sigma-adaptin, the synaptobrevin N-terminal domains sec22 and Ykt6, and the srx domain of the signal recognition particle receptor also regulate vesicle trafficking pathways by mediating SNARE fusion, recognizing specialized compartments, and interacting with small GTPases that resemble Ypt7.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA. lkinch@chop.swmed.edu
authors.forename: Lisa N
authors.initials: LN
authors.lastname: Kinch
authors.forename: Nick V
authors.initials: NV
authors.lastname: Grishin
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry*; D017124:Conserved Sequence; D005057:Eukaryotic Cells / Q000737:chemistry*; D019143:Evolution, Molecular; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D022161:Transport Vesicles / Q000737:chemistry*; D033921:Vesicular Transport Proteins / Q000737:chemistry
chemical_list: D001426:Bacterial Proteins; C441960:Ccz1 protein, S cerevisiae; C516996:DUF254 protein, S cerevisiae; D020662:Guanine Nucleotide Exchange Factors; C102160:HPS1 protein, human; C451752:HPS4 protein, human; D008565:Membrane Proteins; C470635:Mon1 protein, S cerevisiae; D046912:Multiprotein Complexes; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins; C493134:chemotaxis inhibitory protein, Staphylococcus aureus; D020559:Monomeric GTP-Binding Proteins