Structural changes and metal binding by proalbumins and other amino-terminal genetic variants of human serum albumin

Abstract

Proalbumins are rare genetic variants of human serum albumin containing a basic propeptide that is not removed during post-transcriptional processing because of a mutation in the site of excision, an Arg-Arg sequence. We have identified the amino acid substitutions in three different types of proalbumins designated Gainesville, Taipei, and Takefu. The first two proalbumins are identical to previously described proalbumins of the Christchurch and Lille types, respectively, and exhibit the characteristic properties of susceptibility to tryptic cleavage and of lower metal-binding affinity. Takefu is a third type of proalbumin and resists tryptic cleavage because of the substitution Arg-1----Pro. Each of the first two types of proalbumins has been identified in geographically separate, ethnically diverse populations and therefore must have arisen by independent mutations. There is some tendency for mutations in albumin to cluster in the propeptide sequence. Although the substitution His3----Gln in the genetic variant albumin Nagasaki-3 decreases metal-binding affinity, mutations further down the polypeptide chain have no such effect, nor is there any reduction of copper-binding affinity in albumin from patients with Wilson disease.