Alpha-1-antitrypsin: Difference between revisions

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Daniel Seeman, Michal Harel, Alexander Berchansky, Joel L. Sussman

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 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.  <ref>''Biochemistry'', Fifth Edition, p.289.</ref>
-A mutation in the genes coding for A1AT known as the "Z-antitrypsin mutation" can lead to formation of an inactive polymer made up of subunits of this protein.  This polymer builds up in liver cell endoplasmic reticulums leading to cirrhosis of the liver and emphysema.  The mutation is believed to decrease the flexibility of A1AT preventing it from inserting its loop region into its own stretch of beta sheet.  Instead it is suggested that the loop region of one subunit of A1AT inserts into the beta region of another subunit, leading to polymerization.  However this method fails to explain the stability of the complex.  An alternative model suggests that this polymerization is the result of domain swapping<ref name="nature_paper" />.
+A mutation in the genes coding for A1AT known as the "Z-antitrypsin mutation" can lead to formation of an inactive polymer made up of subunits of this protein.  This polymer builds up in liver cell endoplasmic reticulums leading to cirrhosis of the liver and emphysema.  One explanation for this is that a decrease in the flexibility of A1AT is preventing it from inserting its loop region into the same subunit as is necessary for the change in fold observed in Serpins.  This model suggests that the loop region of one subunit of A1AT inserts into the middle of another subunit, leading to polymerization.  However this method fails to explain the stability of the complex.  An alternative model suggests that this polymerization is the result of domain swapping<ref name="nature_paper" />.
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