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Effects of mutations that alter the Glu264-Lys387 salt bridge on the secretion of alpha-1-proteinase inhibitor.

1993; Elsevier BV; Volume: 268; Issue: 9 Linguagem: Inglês

10.1016/s0021-9258(18)53316-0

1083-351X

Robbin Brodbeck, Taraz Samandari, Jennifer Brown,

Glycosylation and Glycoproteins Research

The possibility that low circulating levels of alpha-1-proteinase inhibitor (A1Pi) in individuals homozygous for the S variant result from disruption of a salt bridge between Glu264 and Lys387 was examined. Mutations effecting this salt bridge were constructed by either altering the common M variant cDNA so that Glu264 was replaced by Val to produce the S variant (A1PiV264) or Lys387 was replaced by Arg (A1PiR387), Asn (A1PiN387), Glu (A1PiE387), Gly (A1PiG387), Ile (A1PiI387), or Leu (A1PiL387). Measurements of secretion from transiently transfected COS cells showed that A1PiG387 and A1PiI387 are secreted as well as and at least as rapidly as A1PiM; the S variant and A1PiL387 are secreted to about the same extent as, but somewhat more slowly, than A1PiM; and the variants containing polar or charged residues at position 387 are poorly secreted, and unlike the other variants in this series undergo significant degradation by 2 h of chase. We conclude that the low circulating level of A1PiS is not due to inefficient secretion nor to excessive intracellular degradation of this variant. In addition we suspect that the lack of secretion of variants with Lys387 replaced by other charged or polar residues is due to alteration of a highly conserved sequence near the carboxyl terminus of A1Pi.