P176S polymorphism in Maspin rewires electrostatic interaction that alters Maspin functionality

Abstract

Maspin has been known to regress tumors by inhibiting angiogenesis, however, its roles have been reported to be context and sequence-dependent. There are various proteins and cofactors that bind with maspin possibly explaining the conflicting roles of maspin. Moreover, maspin polymorphic forms have also been linked to tumor regression or survival, for instance, maspin with Ser at 176 (maspin-S176) promotes tumor while maspin with Pro at 176 (maspin-Pro176) has opposing roles in cancer pathogenesis. With the help of long molecular dynamic simulation, a possible link between polymorphic forms and tumor progression has been established. First, the maspin is dynamically stable with either amino acid at 176 position, secondly, differential contacts have been observed among various regions, thirdly, these contacts have significantly altered the electrostatic energetics of various residues, and finally, these altered electrostatics of maspin-S176 and maspin-P176 rewired the polar contacts that abolished the allosteric control in protein. By combining these factors, the altered electrostatics can substantially affect the localization, and the preference of maspin binding partners, thus, culminating in a different maspin-protein (cofactor)-interaction landscape that could have been manifested with conflicting reports in previous studies. Here, the underlying reason has been highlighted and discussed that could be helpful for better therapeutic manipulations. SignificanceProtein altered functions in response to mutations are well documented, however, a slight perturbation in structure can lead to dramatic effects that are being felt at longer distances are rare. Here, we have reported that the substitution of Pro to Ser at 176th position in Maspin can substantially alter the protein electrostatic interactions that can hamper the allosteric control. This could lead to different binding partners, localization preferences, and altered cytoplasmic retention duration resulting in functions that are not associated with normal protein. Moreover, the electrostatic attraction/repulsion can immensely affect the allosteric cohesion of protein resulting in unexpected outcomes.