Effect of Disease Causing Missense Mutations on Intrinsically Disordered Regions in Proteins

Area of Science:

• Biochemistry
• Structural Biology
• Genetics

Background:

• Disease-causing missense mutations (DCMMs) are known to destabilize protein structures.
• The impact of DCMMs on intrinsically disordered regions (IDRs), which lack stable 3D structures, remains poorly understood.
• Investigating DCMMs' effects on IDRs is crucial due to their functional importance.

Purpose of the Study:

• To investigate the impact of known DCMMs on functionally important IDRs in human proteins.
• To elucidate how mutations affect the conformational dynamics of IDRs.

Main Methods:

• Molecular dynamics (MD) simulations were performed for 100ns on wild-type and mutant forms of three specific IDRs.
• The IDRs studied included one with a CRIB motif (WAS protein), a proline-rich IDR (p22 protein), and an IDR with a TRM motif (SH3BP2 protein).

Main Results:

• MD simulations revealed that mutants adopt fewer conformational states compared to wild-type counterparts, with one or two states dominating.
• Free-energy landscapes corroborated these findings, showing fewer minima for mutants.
• New hydrogen bonding interactions introduced by mutated residues stabilize dominant conformational states.

Conclusions:

• DCMMs reduce the conformational heterogeneity of IDRs.
• Mutations can "lock" IDRs into specific conformational states.
• This stabilization likely disfavors the binding of IDRs with their cognate interacting partners.