Mutation in MCL1 predicted loop to helix structural transition
stabilizes MCL1-Bax binding interaction favoring cancer cell survival
Abstract
Myeloid cell leukemia-1 (MCL1), an anti-apoptotic BCL-2 family protein
plays a major role in the control of apoptosis as the regulator of
mitochondrial permeability which is deregulated in various solid and
hematological malignancies. Interaction of the executioner proteins
Bak/Bax with anti-apoptotic MCL1 and its cellular composition determines
the apoptotic or survival pathway. This study highlighted the
deleterious MCL1-Bax stabilizing effect of the mutation V220F on MCL1
structure through computational protein-protein interaction predictions
and molecular dynamics simulations. The single point mutation at V220F
was selected as it is residing at the hydrophobic core region of BH3
conserved domain, the site of Bax binding. The molecular dynamics
simulation studies showed increase in stability of the mutated MCL1
before and after Bax binding comparable with the native MCL1. The
clusters from free energy landscape found out structural variation in
folding pattern with additional helix near the BH3 domain in the mutated
structure. This loop to helix structural change in the mutated complex
favored stable interaction of the complex and also induced Bax
conformational change. Moreover, molecular mechanics based binding free
energy calculations confirmed increased affinity of Bax towards mutated
MCL1. Residue-wise interaction network analysis showed the individual
residues in Bax binding responsible for the change in stability and
interaction due to the protein mutation. In conclusion, the overall
findings from the study reveal that the presence of V220F mutation
on MCL1 is responsible for the structural confirmational change leading
to disruption of its biological functions which might be responsible for
tumorigenesis. The mutation could possibly be used as future diagnostic
markers in treating cancers.