2n3y | pdb_00002n3y
NMR structure of the Y48pCMF variant of human cytochrome c in its reduced state
Structural highlights
Disease[CYC_HUMAN] Defects in CYCS are the cause of thrombocytopenia type 4 (THC4) [MIM:612004]; also known as autosomal dominant thrombocytopenia type 4. Thrombocytopenia is the presence of relatively few platelets in blood. THC4 is a non-syndromic form of thrombocytopenia. Clinical manifestations of thrombocytopenia are absent or mild. THC4 may be caused by dysregulated platelet formation.[1] Function[CYC_HUMAN] Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain. Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases. Publication Abstract from PubMedRegulation of mitochondrial activity allows cells to adapt to changing conditions and to control oxidative stress, and its dysfunction can lead to hypoxia-dependent pathologies such as ischemia and cancer. Although cytochrome c phosphorylation-in particular, at tyrosine 48-is a key modulator of mitochondrial signaling, its action and molecular basis remain unknown. Here we mimic phosphorylation of cytochrome c by replacing tyrosine 48 with p-carboxy-methyl-l-phenylalanine (pCMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around pCMF that could explain changes observed in its functionality: The phosphomimetic mutation impairs cytochrome c diffusion between respiratory complexes, enhances hemeprotein peroxidase and reactive oxygen species scavenging activities, and hinders caspase-dependent apoptosis. Our findings provide a framework to further investigate the modulation of mitochondrial activity by phosphorylated cytochrome c and to develop novel therapeutic approaches based on its prosurvival effects. Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48.,Moreno-Beltran B, Guerra-Castellano A, Diaz-Quintana A, Del Conte R, Garcia-Maurino SM, Diaz-Moreno S, Gonzalez-Arzola K, Santos-Ocana C, Velazquez-Campoy A, De la Rosa MA, Turano P, Diaz-Moreno I Proc Natl Acad Sci U S A. 2017 Apr 11;114(15):E3041-E3050. doi:, 10.1073/pnas.1618008114. Epub 2017 Mar 27. PMID:28348229[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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