title: Identification of a Novel Sequence Motif Recognized by the Ankyrin Repeat Domain of zDHHC17/13 S-Acyltransferases.
abstract: S-Acylation is a major post-translational modification affecting several cellular processes. It is particularly important for neuronal functions. This modification is catalyzed by a family of transmembrane S-acyltransferases that contain a conserved zinc finger DHHC (zDHHC) domain. Typically, eukaryote genomes encode for 7-24 distinct zDHHC enzymes, with two members also harboring an ankyrin repeat (AR) domain at their cytosolic N termini. The AR domain of zDHHC enzymes is predicted to engage in numerous interactions and facilitates both substrate recruitment and S-acylation-independent functions; however, the sequence/structural features recognized by this module remain unknown. The two mammalian AR-containing S-acyltransferases are the Golgi-localized zDHHC17 and zDHHC13, also known as Huntingtin-interacting proteins 14 and 14-like, respectively; they are highly expressed in brain, and their loss in mice leads to neuropathological deficits that are reminiscent of Huntington's disease. Here, we report that zDHHC17 and zDHHC13 recognize, via their AR domain, evolutionary conserved and closely related sequences of a [VIAP][VIT]XXQP consensus in SNAP25, SNAP23, cysteine string protein, Huntingtin, cytoplasmic linker protein 3, and microtubule-associated protein 6. This novel AR-binding sequence motif is found in regions predicted to be unstructured and is present in a number of zDHHC17 substrates and zDHHC17/13-interacting S-acylated proteins. This is the first study to identify a motif recognized by AR-containing zDHHCs.
authors.affiliation: From the Strathclyde Institute of Pharmacy and Biomedical Sciences, Univesity of Strathclyde, Glasgow G4 0RE, United Kingdom.
authors.forename: Kimon
authors.initials: K
authors.lastname: Lemonidis
authors.affiliation: From the Strathclyde Institute of Pharmacy and Biomedical Sciences, Univesity of Strathclyde, Glasgow G4 0RE, United Kingdom.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Sanchez-Perez
authors.affiliation: From the Strathclyde Institute of Pharmacy and Biomedical Sciences, Univesity of Strathclyde, Glasgow G4 0RE, United Kingdom luke.chamberlain@strath.ac.uk.
authors.forename: Luke H
authors.initials: LH
authors.lastname: Chamberlain
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D020816:Amino Acid Motifs / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D017089:Ankyrin Repeat / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002417:Cattle; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D051381:Rats; D017386:Sequence Homology, Amino Acid; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D050956:HSP40 Heat-Shock Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; C491894:MAP6 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D050825:Synaptosomal-Associated Protein 25; C088460:cysteine string protein; D000217:Acyltransferases; C552301:Zdhhc13 protein, mouse; C569387:Zdhhc17 protein, mouse
keywords: Golgi; Huntington disease; S-acylation; ankyrin repeat domain; membrane enzyme; protein palmitoylation; substrate specificity; zDHHC13; zDHHC17