Computer-aided molecular modeling and structural analysis of the human
centromere protein-HIKM complex
Abstract
Protein-peptide and protein-protein interactions play an essential role
in different functional and structural cellular organizational aspects.
While X-ray crystallography generates the most complete structural
characterization, most biological interactions exist in biomolecular
complexes that are neither compliant nor responsive to direct
experimental analysis. The development of computational docking
approaches is therefore necessary. This starts from component protein
structures to the prediction of their complexes, preferentially with
precision close to complex structures generated by X-ray
crystallography. To guarantee faithful chromosomal segregation, there
must be a proper assembling of the kinetochore (a protein complex with
multiple subunits) at the centromere during the process of cell
division. As an important member of the inner kinetochore, defects in
any of the subunits making up the CENP-HIKM complex leads to kinetochore
dysfunction and an eventual chromosomal mis-segregation and cell death.
Previous studies in an attempt to understand the assembly and mechanism
devised by the CENP-HIKM in promoting functionality of the kinetochore,
have reconstituted the protein complex from different organisms
including fungi and yeast. Here, we present a detailed computational
model of the physical interactions that exist between each component of
the human CENP-HIKM, while validating each modeled structure using
orthologs with existing crystal structures from the protein data bank.
Results from this study substantiates the existing hypothesis that the
human CENP-HIK complex share a similar architecture with its fungal and
yeast orthologs, and likewise validates the binding mode of CENP-M to
the C-terminus of the human CENP-I based on existing experimental
reports.