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Journal article
Calcium-Myristoyl Tug Is a New Mechanism for Intramolecular Tuning of Calcium Sensitivity and Target Enzyme Interaction for Guanylyl Cyclase-activating Protein 1: DYNAMIC CONNECTION BETWEEN N-FATTY ACYL GROUP AND EF-HAND CONTROLS CALCIUM SENSITIVITY
The Journal of biological chemistry, v 287(17), pp 13972-13984
20 Apr 2012
PMID: 22383530
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Background:
N
-Myristoylated GCAP1 controls Ca
2+
sensitivity of cGMP synthesis in photoreceptors.
Results:
Hydrophobic residues replacing the myristoyl group in GCAP1 restore activation of its target enzyme but not Ca
2+
binding.
Conclusion:
The fatty chain regulates sensitivity of EF-hand located on the opposite side via intramolecular tug.
Significance:
Mechanisms of Ca
2+
binding by GCAP1 are critical for normal vision and visual disorders.
Guanylyl cyclase-activating protein 1 (GCAP1), a myristoylated Ca
2+
sensor in vision, regulates retinal guanylyl cyclase (RetGC). We show that protein-myristoyl group interactions control Ca
2+
sensitivity, apparent affinity for RetGC, and maximal level of cyclase activation. Mutating residues near the myristoyl moiety affected the affinity of Ca
2+
binding to EF-hand 4. Inserting Phe residues in the cavity around the myristoyl group increased both the affinity of GCAP1 for RetGC and maximal activation of the cyclase. NMR spectra show that the myristoyl group in the L80F/L176F/V180F mutant remained sequestered inside GCAP1 in both Ca
2+
-bound and Mg
2+
-bound states. This mutant displayed much higher affinity for the cyclase but reduced Ca
2+
sensitivity of the cyclase regulation. The L176F substitution improved affinity of myristoylated and non-acylated GCAP1 for the cyclase but simultaneously reduced the affinity of Ca
2+
binding to EF-hand 4 and Ca
2+
sensitivity of the cyclase regulation by acylated GCAP1. The replacement of amino acids near both ends of the myristoyl moiety (Leu
80
and Val
180
) minimally affected regulatory properties of GCAP1.
N
-Lauryl- and
N
-myristoyl-GCAP1 activated RetGC in a similar fashion. Thus, protein interactions with the central region of the fatty acyl chain optimize GCAP1 binding to RetGC and maximize activation of the cyclase. We propose a dynamic connection (or “tug”) between the fatty acyl group and EF-hand 4 via the C-terminal helix that attenuates the efficiency of RetGC activation in exchange for optimal Ca
2+
sensitivity.
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Details
- Title
- Calcium-Myristoyl Tug Is a New Mechanism for Intramolecular Tuning of Calcium Sensitivity and Target Enzyme Interaction for Guanylyl Cyclase-activating Protein 1
- Creators
- Igor V. Peshenko - Salus UniversityElena V. Olshevskaya - Salus UniversitySunghyuk Lim - University of California, DavisJames B. Ames - University of California, DavisAlexander M. Dizhoor - Salus University
- Publication Details
- The Journal of biological chemistry, v 287(17), pp 13972-13984
- Publisher
- American Society for Biochemistry and Molecular Biology
- Number of pages
- 13
- Grant note
- EY11522; EY012347 / National Institutes of Health
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; Pennsylvania College of Optometry (PCO)
- Web of Science ID
- WOS:000303996300052
- Scopus ID
- 2-s2.0-84859967548
- Other Identifier
- 991022035115204721
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- Web of Science research areas
- Biochemistry & Molecular Biology