Identification of a novel sequence motif recognised by the ankyrin-repeat domain of zDHHC17/13 S-acyl-transferases

Kimon Lemonidis, Maria C. Sanchez-Perez, Luke H. Chamberlain

Research output: Contribution to journalArticle

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113 Downloads (Pure)

Abstract

S-acylation is a major post-translational modification affecting several cellular processes and being particularly important for neuronal functions. This modification is catalysed by a family of transmembrane S-acyl-transferases that contain a conserved zinc-finger DHHC (zDHHC) domain. Typically, eukaryote genomes encode for 7-24 distinct zDHHC enzymes, with 2 members also harbouring an ankyrin-repeat (AR) domain at their cytosolic N-terminus. 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 recognised by this module remain unknown. The two mammalian AR-containing S-acyltransferases are the Golgi-localised zDHHC17 and zDHHC13, also known as Huntingtin-interacting proteins 14 and 14-like, respectively; these are highly expressed in brain, and their loss in mice leads to neuropathological deficits that are reminiscent of Huntington disease. Here, we report that zDHHC17 and zDHHC13 recognise 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 recognised by AR-containing zDHHCs.
Original languageEnglish
Number of pages24
JournalJournal of Biological Chemistry
Early online date21 Jul 2015
DOIs
Publication statusPublished - 4 Sep 2015

Fingerprint

Ankyrin Repeat
Transferases
Zinc Fingers
Zinc
Acylation
Acyltransferases
Microtubule-Associated Proteins
Protein S
Huntington Disease
Substrates
Enzymes
Post Translational Protein Processing
Eukaryota
Brain
Consensus
Proteins
Genes
Genome

Keywords

  • Golgi
  • Huntington disease
  • membrane enzyme
  • protein palmitoylation
  • substrate specificity
  • S-acylation
  • ankyrin-repeat domain
  • zDHHC13
  • zDHHC17

Cite this

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title = "Identification of a novel sequence motif recognised by the ankyrin-repeat domain of zDHHC17/13 S-acyl-transferases",
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Identification of a novel sequence motif recognised by the ankyrin-repeat domain of zDHHC17/13 S-acyl-transferases. / Lemonidis, Kimon; Sanchez-Perez, Maria C.; Chamberlain, Luke H.

In: Journal of Biological Chemistry, 04.09.2015.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of a novel sequence motif recognised by the ankyrin-repeat domain of zDHHC17/13 S-acyl-transferases

AU - Lemonidis, Kimon

AU - Sanchez-Perez, Maria C.

AU - Chamberlain, Luke H.

PY - 2015/9/4

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N2 - S-acylation is a major post-translational modification affecting several cellular processes and being particularly important for neuronal functions. This modification is catalysed by a family of transmembrane S-acyl-transferases that contain a conserved zinc-finger DHHC (zDHHC) domain. Typically, eukaryote genomes encode for 7-24 distinct zDHHC enzymes, with 2 members also harbouring an ankyrin-repeat (AR) domain at their cytosolic N-terminus. 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 recognised by this module remain unknown. The two mammalian AR-containing S-acyltransferases are the Golgi-localised zDHHC17 and zDHHC13, also known as Huntingtin-interacting proteins 14 and 14-like, respectively; these are highly expressed in brain, and their loss in mice leads to neuropathological deficits that are reminiscent of Huntington disease. Here, we report that zDHHC17 and zDHHC13 recognise 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 recognised by AR-containing zDHHCs.

AB - S-acylation is a major post-translational modification affecting several cellular processes and being particularly important for neuronal functions. This modification is catalysed by a family of transmembrane S-acyl-transferases that contain a conserved zinc-finger DHHC (zDHHC) domain. Typically, eukaryote genomes encode for 7-24 distinct zDHHC enzymes, with 2 members also harbouring an ankyrin-repeat (AR) domain at their cytosolic N-terminus. 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 recognised by this module remain unknown. The two mammalian AR-containing S-acyltransferases are the Golgi-localised zDHHC17 and zDHHC13, also known as Huntingtin-interacting proteins 14 and 14-like, respectively; these are highly expressed in brain, and their loss in mice leads to neuropathological deficits that are reminiscent of Huntington disease. Here, we report that zDHHC17 and zDHHC13 recognise 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 recognised by AR-containing zDHHCs.

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KW - Huntington disease

KW - membrane enzyme

KW - protein palmitoylation

KW - substrate specificity

KW - S-acylation

KW - ankyrin-repeat domain

KW - zDHHC13

KW - zDHHC17

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DO - 10.1074/jbc.M115.657668

M3 - Article

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

ER -