410 IRON-CONTAINING PROTEINS AND ENZYMES
evolutionary relationships between proteins whose structure is known. It
surveys protein folds, detailed information about close relatives or any par-
ticular protein, and a framework for future research into protein classifi cation
systems.
The Bertini group ’ s work^101 begins by describing the well - known “ cyto-
chrome c fold, ” which usually encompasses three structural elements: (1) N -
and C - terminal α - helices ( α 1 and α 5 in mitochondrial cytochromes); (2) a long
α 3 helix (also called the 60 ’ s helix in mitochondrial cytochromes); followed by
(3) a shortα - helix and loop that contains the heme iron ’ s second axial ligand —
usually a methionine. Alternatively, the heme iron ion ’ s second axial ligand
may be another histidine or an asparagine or may be absent altogether. All
cytochromes c contain a cys – X – X – cys – his (CXXCH) signature sequence for
attaching the heme to the rest of the protein. As stated above, the sulfur atoms
of the cysteine residues provide thioether linkages to vinylic heme carbon
atoms, while the signature histidine provides one axial ligand for heme iron
ion.
Cytochromes c function as electron transfer proteins in aerobic and anaero-
bic respiration, but have a number of other physiological purposes. For instance,
cytochromes c recently have been implicated in apoptosis (cell death) pro-
cesses.^104 Mitochondrial cytochrome c appears to be necessary for the enzyme
cytochrome c oxidase ’ s assembly,^105 although the exact mechanism is unknown.
In eukaryotes, a minor role in hydrogen peroxide scavenging has been assigned
to some cytochrome c ’ s.^106 The H 2 O 2 scavenging role in mammals takes place
through interaction of cytochrome c and cytochrome c peroxidase (CCP).^107
In bacteria, cytochromes c are involved in respiratory processes and in H 2 O 2
scavenging. Often cytochromes c serve as the entry and exit point for electrons
in the catalytic cycle of enzymes to which they are attached. This is the case
for the cytochrome bc 1 complex as discussed in Section 7.6.
The cytochrome c bioinformatic analyses performed by the Bertini group
(reference 101 ) identifi ed 966 cytochrome c domains in 32 Eukaryota, 59
Gram - negative bacteria, 17 Gram - positive bacteria, and four Archaea. To
further reduce the number of cytochromes c described, the authors concen-
trated on proteins containing a single cytochrome c domain. For instance, a
“ typical ” primate mitochondrial cytochrome c is identifi ed as a single - domain,
soluble, 100 - to 110 - residue protein located in the intermembrane space of the
mitochondrion. All mitochondrial cytochromes c are positively charged as
physiological pH and are therefore attracted to (and at least sporadically
attached to) negative domains on partner enzymes such as cytochrome bc 1
complex, cytochrome c oxidase, or cytochrome c peroxidase. During aerobic
respiration, for instance, mitochondrial cytochrome c shuttles electrons from
the bc 1 complex (Section 7.6) to cytochrome c oxidase (CCO or CcO, Section
7.8) in the mitochondrion. Figure 2 of reference 101 and Figure 1 of reference
78 show schematic diagrams illustrating the role of cytochrome c in transfer-
ring electrons from the bc 1 complex to cytochrome c oxidase as well as the
translocation of protons and the connection to ATP (adenosine triphosphate)