Alpha-1-antitrypsin (also known as α1-antitrypsin or A1AT) is an inhibitor of Elastase and Trypsin. It is a member of the Serine Protease Inhibitor (Serpin) family, and as such undergoes a conformational change where the substrate protein associates with a loop region on A1AT causing that loop to become ordered as a Beta Strand[1]. In this case Trypsin (the substrate) is inhibited when a covalent bond is formed to A1AT through the newly formed Beta region[1]. Once bound covalently to its substrate the stability of the A1AT complex goes up drastically[1]. With A1AT, as with most members of the Serpin family, the transition from inactive precursor protein to active complex comes after a cleavage event[1]. Shown is a morph, generated by the Yale Morph Server that shows A1AT going from its inactive form, to the conformation in which it is bound to Trypsin (also shown in the same animation)[2].
Role in diseaseRole in disease
Mutations of MET358 to ARG can lead to a change in specificity in the Elastase binding pocket, essentially turning the M358R mutant of A1AT into a Thrombin inhibitor by generating specificity for this new substrate. This drop in Thrombin levels can lead to hemorrhaging. [3]
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