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Liaison between Myristoylation and Cryptic EF-Hand Motif Confers Ca<sup>2+</sup> Sensitivity to Neuronal Calcium Sensor‑1

By Vangipurapu Rajanikanth (1679857), Anand Kumar Sharma (1679854), Meduri Rajyalakshmi (1679860), Kousik Chandra (1303107), Kandala V. R. Chary (110313) and Yogendra Sharma (234147)

Abstract

Many members of the neuronal calcium sensor (NCS) protein family have a striking coexistence of two characteristics, that is, N-myristoylation and the cryptic EF-1 motif. We investigated the rationale behind this correlation in neuronal calcium sensor-1 (NCS-1) by restoring Ca<sup>2+</sup> binding ability of the disabled EF-1 loop by appropriate mutations. The concurrence of canonical EF-1 and N-myristoylation considerably decreased the overall Ca<sup>2+</sup> affinity, conformational flexibility, and functional activation of downstream effecter molecules (i.e., PI4Kβ). Of a particular note, Ca<sup>2+</sup> induced conformational change (which is the first premise for a CaBP to be considered as sensor) is considerably reduced in myristoylated proteins in which Ca<sup>2+</sup>-binding to EF-1 is restored. Moreover, Ca<sup>2+</sup>, which otherwise augments the enzymatic activity of PI4Kβ (modulated by NCS-1), leads to a further decline in the modulated PI4Kβ activity by myristoylated mutants (with canonical EF-1) pointing toward a loss of Ca<sup>2+</sup> signaling and specificity at the structural as well as functional levels. This study establishes the presence of the strong liaison between myristoylation and cryptic EF-1 in NCS-1. Breaking this liaison results in the failure of Ca<sup>2+</sup> specific signal transduction to downstream effecter molecules despite Ca<sup>2+</sup> binding. Thus, the EF-1 disability is a prerequisite in order to append myristoylation signaling while preserving structural robustness and Ca<sup>2+</sup> sensitivity/specificity in NCS-1

Topics: Biophysics, Biochemistry, Molecular Biology, Neuroscience, Physiology, Computational Biology, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Physical Sciences not elsewhere classified, EF, PI 4K activity, liaison, calcium sensor, effecter molecules, NCS
Year: 2015
DOI identifier: 10.1021/bi501134g.s001
OAI identifier: oai:figshare.com:article/2210830
Provided by: FigShare
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