Reference

PortadaPNAS11227DOI:10.1073/pnas.1506538112

Authors

Irene Garcia-Ferrer; Pedro Arêde; Josué G ómez-Blanco; Daniel Luque; Stephane Durrequoi; José R. Castón; Theodoros Goulas and F. Xavier Gomis-Rüth

Abstract

The survival of commensal bacteria requires them to evade host peptidases. Gram-negative bacteria from the human gut microbiome encode a relative of the human endopeptidase inhibitor, α2-macroglobulin (α2M). Escherichia coli α2M (ECAM) is a ∼ 180-kDa multidomain membrane-anchored pan-peptidase inhibitor, which is cleaved by host endopeptidases in an accessible bait region. Structural studies by electron microscopy and crystallography reveal that this cleavage causes major structural rearrangement of more than half the 13-domain structure from a native to a compact induced form. It also exposes a reactive thioester bond, which covalently traps the peptidase. Subsequently, peptidase-laden ECAM is shed from the membrane and may dimerize. Trapped peptidases are still active except against very large substrates, so inhibition potentially prevents damage of large cell envelope components, but not host digestion. Mechanistically, these results document a novel monomeric "snap trap."

Description

Las bacterias comensales que forman parte del microbioma humano deben sobrevivir en presencia de encimas digestivas provenientes del huésped y por lo tanto poseen mecanismos para combatir la acción nociva de dichas moléculas. Así, Escherichia coli codifica en su genoma una proteína homóloga a la α2-macroglobulina humana, un inhibidor de proteasas presente en el plasma sanguíneo. Este homólogo bacteriano, nombrado ECAM, es una proteína multidominio de 180 kDa que se encuentra en el periplasma bacteriano, anclado a la membrana interna de E.coli. Estudios funcionales han permitido probar su actividad como inhibidor de proteasas, así como relacionar su función con mecanismos de protección celular en E.coli. Además, se ha descrito un nuevo mecanismo de inhibición de proteasas por el cual esta proteína ejerce su función, nombrado mecanismo snap-trap, el cual podría ser utilizado por otras α2-macroglobulinas monoméricas. La caracterización estructural de ECAM, tanto por cristalografía de rayos X como por crio-microscopía electrónica, ha permitido identificar y describir elementos estructurales claves en este mecanismo.

 

GrupInvest

 

REFERENCIA DEL GRUPO INVESTIGADOR

Proteolysis lab es un grupo de investigación liderado por el Prof. F.X. Gomis-Rüth y establecido en el Instituto de Biología Molecular de Barcelona (IBMB-CSIC). El trabajo realizado en el grupo está centrado en el análisis de proteínas, principalmente peptidasas y sus inhibidores, tanto proteicos como de molécula pequeña. Para ello se emplean técnicas de biología molecular, caracterización biofísica de proteínas y cristalografía de rayos X, entre otras. El objetivo principal es entender la relación entre la estructura y la función de dichas proteínas, especialmente de aquellas relacionadas con mecanismos de virulencia bacteriana, con el fin de proporcionar información molecular necesaria para el diseño de nuevos fármacos.

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