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 ofsusceptibility to tryptic cleavage and of lower metal-binding affinity. Takefu is a third

Point substitutions in Japanese alloalbumins.

“…An unambiguous sequence characteristic of the Christchurch type of proalbumin was obtained: Arg-Gly-Val-PheArg-Gln-Asp-Ala-His-Lys. In this sequence glutamine replaces the last arginine in the proalbumin hexapeptide aminoterminal sequence (-1 Arg--Gln) (11,16). This accords with the single-base mutation CGA to CAA.…”

“…In the present work the five variants were compared at pH 4.0 and 5.6 with reference alloalbumins for which the substitution was known. The reference variants with known substitutions are albumin Mexico (slow + 1, 550 Asp Gly) (10), albumin B Lubeck (slow +2, 570 Glu -* Lys) (15), and proalbumin Pollibauer (Lille type, slow +2, -2 Arg -+ His) (11). The five Japanese variants showed different combinations of mobilities in the two buffer systems; all were also different from albumin B and proallbumin Pollibauer.…”

“…Including the results reported here, a total of 18 different sites of substitution of a single amino acid have been recorded within the mature human albumin molecule, which contains 585 amino acid residues (4, 10-15, 17-21); all can be explained by change of a single base in the corresponding codon. Three similar point mutations at two sites occur in the hexapeptide propeptide at the amino terminus (11,15,16) as well as one frame shift at the carboxyl terminus (18). Of the 18 point mutation sites in the mature albumin molecule, only 5 occur in the first 353 residues, whereas 7 are in the sequence of 29 amino acids from position 354 through 382 illustrated in Fig.…”

“…For want of structural information such variants generally have been assigned ethnic or geographical names. Recently we (4,(9)(10)(11)(12)(13)(14)(15) and others (16)(17)(18)(19)(20)(21) have determined the structural change in a number of variant albumins. We have now completed the structural study of the five rare types of inherited albumin variants discovered in the Biochemical Genetics Study of the Radiation Effects Research Foundation (RERF); this surveyed some 30 blood and plasma polypeptides in a cohort of 15,581 unrelated children in Nagasaki and Hiroshima (2).…”

Calcium‐dependent KEX2‐like protease found in hepatic secretory vesicles converts proalbumin to albumin

“…The existence of the circulating variants, proalbumin Christchurch (-1 Arg~Gln) [7], proalbumin Lille ( -2 Arg -~ His) [8], and proalbumin Takefu (-1 Arg ~ Pro) [9] establish a critical requirement for a pair of basic residues at the [10]. Here the reactive center, or 'bait', of the inhibitor had mutated to Arg, thereby directing it against arginyl-specific proteases, demonstrably targeting it against thrombin and, by implication, against the proalbumin-cleaving enzyme [11].…”