4.6 Article

Activation and inhibition of photoreceptor guanylyl cyclase by guanylyl cyclase activating protein 1 (GCAP-1)

期刊

JOURNAL OF BIOLOGICAL CHEMISTRY
卷 282, 期 30, 页码 21645-21652

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AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M702368200

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  1. NEI NIH HHS [EY11522, R01 EY011522, R01 EY011522-12] Funding Source: Medline

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Guanylyl cyclase activating protein 1 (GCAP-1), a Ca2+/Mg2+ sensor protein that accelerates retinal guanylyl cyclase (RetGC) in the light and decelerates it in the dark, is inactive in cation-free form. Binding of Mg2+ in EF-hands 2 and 3 was essential for RetGC activation in the conditions mimicking light adaptation. Mg2+ binding in EF-hand 2 affected the conformation of a neighboring non-metal binding domain, EF-hand-1, and increased GCAP-1 affinity for RetGC nearly 40-fold compared with the metal-free EF-hand 2. Mg2+ binding in EF-hand 3 increased GCAP-1 affinity for RetGC 5-fold and its maximal RetGC stimulation 2-fold. Mg2+ binding in EF-hand 4 affected neither GCAP-1 affinity for RetGC, nor RetGC activation. Inactivation of Ca2+ binding in EF-hand 4 was sufficient to render GCAP-1 a constitutive activator of RetGC, whereas the EF-hand 3 role in Ca2+-dependent deceleration of RetGC was likely to be through the neighboring EF-hand 4. Inactivation of Ca2+ binding in EF-hand 2 affected cooperativity of RetGC inhibition by Ca2+, but did not prevent the inhibition. We conclude that 1) Mg2+ binding in EF-hands 2 and 3, but not EF-hand 4, is essential for the ability of GCAP-1 to activate RetGC in the light; 2) Mg2+ or Ca2+ binding in EF-hand 3 and especially in EF-hand 2 is required for high-affinity interaction with the cyclase and affects the conformation of the neighboring EF-hand 1, a domain required for targeting RetGC; and 3) RetGC inhibition is likely to be primarily caused by Ca2+ binding in EF-hand 4.

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