期刊
ACS OMEGA
卷 7, 期 13, 页码 11510-11518出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.2c01256
关键词
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资金
- National Natural Science Foundation of China [21977042, 32171270]
Human cytochrome c plays a crucial role in energy conversion and intrinsic apoptosis pathways. This study reveals that Ile81 not only suppresses the intrinsic peroxidase activity, but also interacts with neuroglobin. Mutations in Ile81 affect this interaction.
Human cytochrome c (hCyt c) is a crucial heme protein and plays an indispensable role in energy conversion and intrinsic apoptosis pathways. The sequence and structure of Cyt c were evolutionarily conserved and only a few naturally occurring mutants were detected in humans. Among those variable sites, position 81 was proposed to act as a peroxidase switch in the initiation stages of apoptosis. In this study, we show that Ile81 not only suppresses the intrinsic peroxidase activity but also is essential for Cyt c to interact with neuroglobin (Ngb), a potential protein partner. The kinetic assays showed that the peroxidase activity of the naturally occurring variant I81N was enhanced up to threefold under pH 5. The local stability of the O-loop D (residues 70-85) in the I81N variant was decreased. Moreover, the Alphafold2 program predicted that Ile81 forms stable contact with human Ngb. Meanwhile, the Ile81 to Asn81 missense mutation abolishes the interaction interface, resulting in a similar to 40-fold decrease in binding affinity. These observations provide an insight into the structure-function relationship of the conserved Ile81 in vertebrate Cyt c.
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