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      Peptide array-based screening reveals a large number of proteins interacting with the ankyrin-repeat domain of the zDHHC17 S-acyltransferase

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          Abstract

          zDHHC S-acyltransferases are enzymes catalyzing protein S-acylation, a common post-translational modification on proteins frequently affecting their membrane targeting and trafficking. The ankyrin repeat (AR) domain of zDHHC17 (HIP14) and zDHHC13 (HIP14L) S-acyltransferases, which is involved in both substrate recruitment and S-acylation-independent functions, was recently shown to bind at least six proteins, by specific recognition of a consensus sequence in them. To further refine the rules governing binding to the AR of zDHHC17, we employed peptide arrays based on zDHHC AR-binding motif (zDABM) sequences of synaptosomal-associated protein 25 (SNAP25) and cysteine string protein α (CSPα). Quantitative comparisons of the binding preferences of 400 peptides allowed us to construct a position-specific scoring matrix (PSSM) for zDHHC17 AR binding, with which we predicted and subsequently validated many putative zDHHC17 interactors. We identified 95 human zDABM sequences with unexpected versatility in amino acid usage; these sequences were distributed among 90 proteins, of which 62 have not been previously implicated in zDHHC17/13 binding. These zDABM-containing proteins included all family members of the SNAP25, sprouty, cornifelin, ankyrin, and SLAIN-motif containing families; seven endogenous Gag polyproteins sharing the same binding sequence; and several proteins involved in cytoskeletal organization, cell communication, and regulation of signaling. A dozen of the zDABM-containing proteins had more than one zDABM sequence, whereas isoform-specific binding to the AR of zDHHC17 was identified for the Ena/VASP-like protein. The large number of zDABM sequences within the human proteome suggests that zDHHC17 may be an interaction hub regulating many cellular processes.

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          Most cited references52

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          The SPOT-synthesis technique. Synthetic peptide arrays on membrane supports--principles and applications.

          Presented first in 1990 at the 21st European Peptide Symposium in Barcelona, Spain [Frank, R., Güler, S., Krause, S., Lindenmaier, W., 1991. Facile and rapid 'spot synthesis' of large numbers of peptides on membrane sheets. In: Giralt, E., Andreu, D. (Eds.) Peptides 1990, Proc. 21st Eur. Peptide Symp. ESCOM, Leiden, p. 151.], the SPOT-synthesis method opened up countless opportunities to synthesise and subsequently screen large numbers of synthetic peptides as well as other organic compounds arrayed on a planar cellulose support [Tetrahedron 48 (1992) 9217]. Already in 1991, a commercial kit for manual SPOT-synthesis became available through Cambridge Research Biochemicals (CRB, UK), and in 1993, a semi-automated SPOT-synthesiser, the ASP222, was launched by ABIMED Analysen-Technik, Germany. Both made the technique available to many research laboratories, even those not experienced in or equipped for chemistry. Although SPOT-synthesis is not as impressively miniaturised as, e.g. the Affymax photolithographic technique [Science 251 (1991) 767], it fulfils similar demands with the advantage of a reliable and easy experimental procedure, inexpensive equipment needs and a highly flexible array and library formatting. The method permits rapid and highly parallel synthesis of huge numbers of peptides and peptide mixtures (pools) including a large variety of unnatural building blocks, as well as a growing range of other organic compounds. Further advantages are related to the easy adaptability to a wide range of assay and screening methods such as binding, enzymatic and cellular assays, which allow in situ screening of chemical libraries due to the special properties of the membrane supports. Therefore, peptide arrays prepared by the SPOT-technique became quite popular tools for studying numerous aspects of molecular recognition, particularly in the field of molecular immunology.
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            Spred is a Sprouty-related suppressor of Ras signalling.

            Cellular proliferation, and differentiation of cells in response to extracellular signals, are controlled by the signal transduction pathway of Ras, Raf and MAP (mitogen-activated protein) kinase. The mechanisms that regulate this pathway are not well known. Here we describe two structurally similar tyrosine kinase substrates, Spred-1 and Spred-2. These two proteins contain a cysteine-rich domain related to Sprouty (the SPR domain) at the carboxy terminus. In Drosophila, Sprouty inhibits the signalling by receptors of fibroblast growth factor (FGF) and epidermal growth factor (EGF) by suppressing the MAP kinase pathway. Like Sprouty, Spred inhibited growth-factor-mediated activation of MAP kinase. The Ras-MAP kinase pathway is essential in the differentiation of neuronal cells and myocytes. Expression of a dominant negative form of Spred and Spred-antibody microinjection revealed that endogenous Spred regulates differentiation in these types of cells. Spred constitutively associated with Ras but did not prevent activation of Ras or membrane translocation of Raf. Instead, Spred inhibited the activation of MAP kinase by suppressing phosphorylation and activation of Raf. Spred may represent a class of proteins that modulate Ras-Raf interaction and MAP kinase signalling.
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              Structural basis and sequence rules for substrate recognition by Tankyrase explain the basis for cherubism disease.

              The poly(ADP-ribose)polymerases Tankyrase 1/2 (TNKS/TNKS2) catalyze the covalent linkage of ADP-ribose polymer chains onto target proteins, regulating their ubiquitylation, stability, and function. Dysregulation of substrate recognition by Tankyrases underlies the human disease cherubism. Tankyrases recruit specific motifs (often called RxxPDG "hexapeptides") in their substrates via an N-terminal region of ankyrin repeats. These ankyrin repeats form five domains termed ankyrin repeat clusters (ARCs), each predicted to bind substrate. Here we report crystal structures of a representative ARC of TNKS2 bound to targeting peptides from six substrates. Using a solution-based peptide library screen, we derive a rule-based consensus for Tankyrase substrates common to four functionally conserved ARCs. This 8-residue consensus allows us to rationalize all known Tankyrase substrates and explains the basis for cherubism-causing mutations in the Tankyrase substrate 3BP2. Structural and sequence information allows us to also predict and validate other Tankyrase targets, including Disc1, Striatin, Fat4, RAD54, BCR, and MERIT40. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                J Biol Chem
                J. Biol. Chem
                jbc
                jbc
                JBC
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology (11200 Rockville Pike, Suite 302, Rockville, MD 20852-3110, U.S.A. )
                0021-9258
                1083-351X
                20 October 2017
                7 September 2017
                7 September 2017
                : 292
                : 42
                : 17190-17202
                Affiliations
                From []The Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE and
                the [§ ]Institute of Cardiovascular and Medical Sciences, University of Glasgow, Wolfson Link Building, Glasgow G12 8QQ, Scotland, United Kingdom
                Author notes
                [1 ] To whom correspondence may be addressed. E-mail: kimon.lemonidis@ 123456strath.ac.uk .
                [2 ] To whom correspondence may be addressed. E-mail: luke.chamberlain@ 123456strath.ac.uk .

                Edited by Henrik G. Dohlman

                Article
                M117.799650
                10.1074/jbc.M117.799650
                5655499
                28882895
                df8845e8-6f81-4c7b-a5c6-ceb5ed9f49f3
                © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

                Author's Choice—Final version free via Creative Commons CC-BY license.

                History
                : 30 May 2017
                : 29 August 2017
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council , open-funder-registry 10.13039/501100000268;
                Award ID: BB/L022087/1
                Award ID: BB/J006432/1
                Categories
                Cell Biology

                Biochemistry
                cytoskeleton,enzyme,peptide array,protein palmitoylation,protein-protein interaction,ankyrin-repeat domain,zdabm,zdhhc13,zdhhc17

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