5O10

Y48H mutant of human cytochrome c

Summary for 5O10

• Entry DOI: 10.2210/pdb5o10/pdb
• Descriptor: Cytochrome c, HEME C (3 entities in total)
• Functional Keywords: heme, haem, cytochrome c, metalloprotein, electron transfer, apoptosis
• Biological source: Homo sapiens (Human)
• Cellular location: Mitochondrion intermembrane space: P99999
• Total number of polymer chains: 2
• Total formula weight: 24468.12

Authors

Moreno-Chicano, T.,Deacon, O.M.,Hough, M.A.,Worrall, J.A.R. (deposition date: 2017-05-17, release date: 2018-03-28, Last modification date: 2024-10-23)

Primary citation

Deacon, O.M.,Karsisiotis, A.I.,Moreno-Chicano, T.,Hough, M.A.,Macdonald, C.,Blumenschein, T.M.A.,Wilson, M.T.,Moore, G.R.,Worrall, J.A.R.
Heightened Dynamics of the Oxidized Y48H Variant of Human Cytochrome c Increases Its Peroxidatic Activity.
Biochemistry, 56:6111-6124, 2017

PubMed Abstract: Proteins performing multiple biochemical functions are called "moonlighting proteins" or extreme multifunctional (EMF) proteins. Mitochondrial cytochrome c is an EMF protein that binds multiple partner proteins to act as a signaling molecule, transfers electrons in the respiratory chain, and acts as a peroxidase in apoptosis. Mutations in the cytochrome c gene lead to the disease thrombocytopenia, which is accompanied by enhanced apoptotic activity. The Y48H variant arises from one such mutation and is found in the 40-57 Ω-loop, the lowest-unfolding free energy substructure of the cytochrome c fold. A 1.36 Å resolution X-ray structure of the Y48H variant reveals minimal structural changes compared to the wild-type structure, with the axial Met80 ligand coordinated to the heme iron. Despite this, the intrinsic peroxidase activity is enhanced, implying that a pentacoordinate heme state is more prevalent in the Y48H variant, corroborated through determination of a Met80 "off rate" of >125 s compared to a rate of ∼6 s for the wild-type protein. Heteronuclear nuclear magnetic resonance measurements with the oxidized Y48H variant reveal heightened dynamics in the 40-57 Ω-loop and the Met80-containing 71-85 Ω-loop relative to the wild-type protein, illustrating communication between these substructures. Placed into context with the G41S cytochrome c variant, also implicated in thrombocytopenia, a dynamic picture associated with this disease relative to cytochrome c is emerging whereby increasing dynamics in substructures of the cytochrome c fold serve to facilitate an increased population of the peroxidatic pentacoordinate heme state in the following order: wild type < G41S < Y48H.

PubMed: 29083920
DOI: 10.1021/acs.biochem.7b00890

Experimental method

X-RAY DIFFRACTION (1.36 Å)