Solution structure of S100A1 bound to the CapZ peptide (TRTK12).

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TitleSolution structure of S100A1 bound to the CapZ peptide (TRTK12).
Publication TypeJournal Article
Year of Publication2009
AuthorsWright, NT, Cannon, BR, Wilder, PT, Morgan, MT, Varney, KM, Zimmer, DB, Weber, DJ
JournalJ Mol Biol
Volume386
Issue5
Pagination1265-77
Date Published2009 Mar 13
ISSN1089-8638
KeywordsBinding Sites, Calcium, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Oligopeptides, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, S100 Proteins
Abstract

As is typical for S100-target protein interactions, a Ca 2+-dependent conformational change in S100A1 is required to bind to a 12-residue peptide (TRTK12) derived from the actin-capping protein CapZ. In addition, the Ca 2+-binding affinity of S100A1 is found to be tightened (greater than threefold) when TRTK12 is bound. To examine the biophysical basis for these observations, we determined the solution NMR structure of TRTK12 in a complex with Ca 2+-loaded S100A1. When bound to S100A1, TRTK12 forms an amphipathic helix (residues N6 to S12) with several favorable hydrophobic interactions observed between W7, I10, and L11 of the peptide and a well-defined hydrophobic binding pocket in S100A1 that is only present in the Ca 2+-bound state. Next, the structure of S100A1-TRTK12 was compared to that of another S100A1-target complex (i.e., S100A1-RyRP12), which illustrated how the binding pocket in Ca 2+-S100A1 can accommodate peptide targets with varying amino acid sequences. Similarities and differences were observed when the structures of S100A1-TRTK12 and S100B-TRTK12 were compared, providing insights regarding how more than one S100 protein can interact with the same peptide target. Such comparisons, including those with other S100-target and S100-drug complexes, provide the basis for designing novel small-molecule inhibitors that could be specific for blocking one or more S100-target protein interactions.

Alternate JournalJ. Mol. Biol.
PubMed ID19452629
PubMed Central IDPMC2768541
Grant ListCA107331 / CA / NCI NIH HHS / United States
GM58888 / GM / NIGMS NIH HHS / United States
R01 CA107331-01A3 / CA / NCI NIH HHS / United States
R01 CA107331-02 / CA / NCI NIH HHS / United States
R01 CA107331-03 / CA / NCI NIH HHS / United States
R01 GM058888-09 / GM / NIGMS NIH HHS / United States
R01 GM058888-10 / GM / NIGMS NIH HHS / United States
R01 GM058888-11 / GM / NIGMS NIH HHS / United States
R01 GM058888-11S1 / GM / NIGMS NIH HHS / United States
S10 RR015741-01 / RR / NCRR NIH HHS / United States
S10 RR016812-01 / RR / NCRR NIH HHS / United States
S10 RR023447-01 / RR / NCRR NIH HHS / United States
S10 RR10441 / RR / NCRR NIH HHS / United States
S10 RR15741 / RR / NCRR NIH HHS / United States
S10 RR16812 / RR / NCRR NIH HHS / United States
S10 RR23447 / RR / NCRR NIH HHS / United States
T32 AR007592 / AR / NIAMS NIH HHS / United States