{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZDHHC17, also known as HIP14, is a highly conserved palmitoyl acyltransferase that catalyzes the reversible attachment of palmitate to specific cysteine residues within substrate proteins. Through its unique ankyrin repeat domain, ZDHHC17 selectively recognizes protein targets bearing cysteine‐rich motifs, thereby regulating their subcellular localization and function. In one study, for example, the enzyme was shown to preferentially palmitoylate a dicysteine motif within the STREX insert of BK channels, highlighting its substrate specificity (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond ion channels, ZDHHC17 is implicated in diverse cellular processes. One report demonstrated that HIP14/HIP14L not only function as protein acyltransferases but also mediate electrogenic, voltage‐dependent magnesium uptake—a role that is modulated by the enzyme’s autopalmitoylation activity (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Furthermore, in pancreatic β‐cells, ZDHHC17 expression is critical for cell survival and glucose‐stimulated insulin secretion; here, downregulation of the protein by proinflammatory cytokines contributes to β‐cell apoptosis (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe enzyme’s function also has important implications in disease. In glioblastoma multiforme, ZDHHC17 is up‐regulated and engages in a signaling module with MAP2K4 and p38/JNK that drives tumorigenicity and supports glioma stem cell self‐renewal—findings that further suggest a potential therapeutic target via disruption of this complex with agents such as genistein (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In the context of neurodegeneration, altered interactions between mutant huntingtin and ZDHHC17, as well as its homolog HIP14L, lead to decreased palmitoylation of huntingtin and other substrates, contributing to protein mislocalization, aggregation, and neuronal toxicity observed in Huntington disease (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and substrate‐selectivity analyses further illuminate ZDHHC17’s role as an interaction hub. Detailed studies employing peptide arrays and crystallography have revealed that its ankyrin repeat domain directly binds segments of client proteins such as Snap25b and ClipR-59—with specific cysteine residues in these substrates being targeted for palmitoylation. In particular, one investigation identified ZDHHC17 as the major palmitoyltransferase for ClipR-59, reinforcing the concept that ZDHHC17 governs the plasma membrane association and function of its substrates (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Moreover, yeast two-hybrid analyses have demonstrated a significant overlap between ZDHHC17's interactome and huntingtin interactors, underscoring its central role in regulating neuronal protein palmitoylation (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lijun Tian, Heather McClafferty, Owen Jeffries, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multiple palmitoyltransferases are required for palmitoylation-dependent regulation of large conductance calcium- and voltage-activated potassium channels."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.137802"}], "href": "https://doi.org/10.1074/jbc.M110.137802"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20507996"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20507996"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Angela Goytain, Rochelle M Hines, Gary A Quamme "}, {"type": "b", "children": [{"type": "t", "text": "Huntingtin-interacting proteins, HIP14 and HIP14L, mediate dual functions, palmitoyl acyltransferase and Mg2+ transport."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M801469200"}], "href": "https://doi.org/10.1074/jbc.M801469200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18794299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18794299"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lukas Adrian Berchtold, Zenia Marian Størling, Fernanda Ortis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and beta-cell apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1104384108"}], "href": "https://doi.org/10.1073/pnas.1104384108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21705657"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21705657"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xueran Chen, Aijun Hao, Xian Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activation of JNK and p38 MAPK Mediated by ZDHHC17 Drives Glioblastoma Multiforme Development and Malignant Progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Theranostics (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/thno.40076"}], "href": "https://doi.org/10.7150/thno.40076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31938047"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31938047"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Shaun S Sanders, Michael R Hayden "}, {"type": "b", "children": [{"type": "t", "text": "Aberrant palmitoylation in Huntington disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Soc Trans (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BST20140242"}], "href": "https://doi.org/10.1042/BST20140242"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25849918"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25849918"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shaun S Sanders, Katherine K N Mui, Liza M Sutton, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Structural Basis for Substrate Recognition by the Ankyrin Repeat Domain of Human DHHC17 Palmitoyltransferase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2017.06.018"}], "href": "https://doi.org/10.1016/j.str.2017.06.018"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28757145"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28757145"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Stefanie L Butland, Shaun S Sanders, Mandi E Schmidt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddu137"}], "href": "https://doi.org/10.1093/hmg/ddu137"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24705354"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24705354"}]}]}]}