P176S Mutation Rewires Electrostatic Interactions That Alter Maspin Functionality

Maspin is known to regress tumors by inhibiting angiogenesis;however,its roles have been reported to be context- and sequence-dependent.Various proteins and cofactors bind to maspin, possibly explainingits conflicting roles. Moreover, polymorphic forms of maspin havealso been linked to tumor regression and survival; for instance, maspinwith Ser at 176 (maspin-S176) promotes tumors, while maspin with Proat 176 (maspin-P176) has opposing roles in cancer pathogenesis. Withthe help of long molecular dynamics simulations, a possible link betweenpolymorphic forms and tumor progression has been established. First,maspin is dynamically stable with either amino acid at the 176 position.Second, differential contacts have been observed among various regions;third, these contacts have significantly altered the electrostaticenergetics of various residues; finally, these altered electrostaticsof maspin-S176 and maspin-P176 rewire the polar contacts that abolishedthe allosteric control of the protein. By combining these factors,the altered electrostatics substantially affect the localization andpreference of maspin-binding partners, thus culminating in a differentmaspin-protein(cofactor)-interaction landscape that may have beenmanifested in previous conflicting reports. Here, the underlying reasonhas been highlighted and discussed, which may be helpful for bettertherapeutic manipulation.

Automated summary

Maspin is a protein that regresses tumors by inhibiting angiogenesis, but its effects depend on the context and sequence. Various proteins and cofactors bind to maspin, which may explain its conflicting roles. Polymorphic forms of maspin have also been linked to tumor regression and survival, with different amino acids at position 176 having opposing effects in cancer development. Molecular dynamics simulations have revealed a possible link between polymorphic forms and tumor progression, showing that altered electrostatics affect the localization and preference of maspin-binding partners, leading to different maspin-protein(companion)-interaction landscapes.