Effect of the Z mutation on the physical and inhibitory properties of alpha 1-antitrypsin

Biochemistry. 1993 Jan 19;32(2):500-8. doi: 10.1021/bi00053a014.


A major feature of the structure of alpha 1-antitrypsin is a five-stranded A-sheet into which the reactive center loop inserts after cleavage. We describe here the effect of the Z mutation (342Glu to Lys) at the head of the fifth strand of the A-sheet on the mobility of the reactive center loop and hence on the physical properties of the antitrypsin molecule. The mutant Z but not the normal M antitrypsin spontaneously polymerizes at 37 degrees C by a mechanism involving the insertion of the reactive center loop of one molecule into the A-sheet of a second. It is demonstrated that Z antitrypsin polymerized after incubation with 1.0 M guanidinium chloride at 37 degrees C at the same rate as M antitrypsin. Reducing the temperature to 4 degrees C favored the formation of the L-state in M antitrypsin in which the loop is stably incorporated into the A-sheet, but resulted in loop-sheet polymerization in Z antitrypsin. Z, like M antitrypsin, undergoes the S to R transition, but we show that the accompanying change in thermal stability results from loop-sheet polymerization (S) which can be prevented by the insertion of the cleaved strand of the reactive center loop into the A-sheet (R). Z antitrypsin has a reduced association rate constant with neutrophil elastase [(5.3 +/- 0.06) x 10(7) and (1.2 +/- 0.02) x 10(7) M-1 s-1 for M and Z, respectively], but both M and Z antitrypsin had Ki values of less than 5 pM.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Chymotrypsin / metabolism
  • Circular Dichroism
  • Hot Temperature
  • Humans
  • Hydrolysis
  • Kinetics
  • Leukocyte Elastase
  • Molecular Sequence Data
  • Mutation*
  • Pancreatic Elastase / antagonists & inhibitors
  • Polymers / chemistry
  • alpha 1-Antitrypsin / chemistry
  • alpha 1-Antitrypsin / genetics*
  • alpha 1-Antitrypsin / isolation & purification
  • alpha 1-Antitrypsin / metabolism


  • Polymers
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin
  • Chymotrypsin
  • Pancreatic Elastase
  • Leukocyte Elastase