TMPRSS11a as a new target in aging

Abstract

Aging is a natural process, that is associated with changes in dynamic biological, physiological, environmental, psychological, behavioral, and social processes. In fact, advancing age is the major risk factor for several chronic diseases in humans. During our study of impaired wound healing in aged models, we analyzed skin lysates of young and old mice by LC‐MS/MS to identify age‐related changes in the proteome. Within the proteins whose levels vary during aging we identified TMPRSS11a, a protein that is overexpressed in aged skin. Transmembrane protease serine 11a (TMPRSS11a, gene ECRG1) is an enzyme, which play a role in cellular senescence and may play a role in SARS‐CoV2 infection. This protein has been described at the enzymatic level, but its three‐dimensional structure and interactome, also its physiological role in the cell, are still unknown. This protease features three clearly defined domains: Peptidase S1, SEA and cytoplasmic domain. Interestingly, within the structure we have detected two sequences of interest, such as the RGD motif, necessary to interact with integrins and an ITIM sequence involved in immunological activation. Through computational analysis we found that the Peptidase domain contains the hydrophobic pocket that inside it presents the classic catalytic triad (H230, D275 and S371) and next to the catalytic serine there is a RGD motif that meets the characteristics of the canonical motif. Interestingly, using molecular dynamics, docking and proximity ligation assay, we found that the RGD motif is functional and allows direct interaction with integrin β1 and this RGD motif of TMPRSS11a binds directly to the site adjacent to MIDAS in the integrin β1. Finally, we evaluated cellular spreading of HEK293 cells, seeded over a fibronectin matrix, and cell migration through trans well migration assays. And in this way, TMPRSS11a may affect processes such as migration or cell adhesion in an RGD‐dependent manner. The expression of this protease could affect processes of vital importance such as wound healing in old animal models. Considering our results, the study of this protein can be used as new therapeutic target of aging.