期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 25, 页码 17812-17829出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.534750
关键词
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资金
- National Institutes of Health [1DP2 CA186752-01]
- American Heart Association [13SDG14270009]
- MCubed program at the University of Michigan
Signaling proteins comprised of modular domains have evolved along with multicellularity as a method to facilitate increasing intracellular bandwidth. The effects of intramolecular interactions between modular domains within the context of native proteins have been largely unexplored. Here we examine intra-and intermolecular interactions in the multidomain signaling protein, protein kinase C alpha (PKC alpha). We identify three interactions between two activated PKC molecules that synergistically stabilize a nanomolar affinity homodimer. Disruption of the homodimer results in a loss of PKC-mediated ERK1/2 phosphorylation, whereas disruption of the auto-inhibited state promotes the homodimer and prolongs PKC membrane localization. These observations support a novel regulatory mechanism wherein homodimerization dictates the equilibrium between the auto-inhibited and active states of PKC by sequestering auto-inhibitory interactions. Our findings underscore the physiological importance of context-dependent modular domain interactions in cell signaling.
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