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Proteolytic Cleavage of Human Chromogranin A Containing Naturally Occurring Catestatin Variants: Differential Processing at Catestatin Region by Plasmin

Departments of Medicine (N.B., S.M.V., M.M., M.D., J.R.G., L.T., D.T.O’C., S.K.M.), of Chemistry and Biochemistry (J.W.T.), and of Molecular Genetics (D.T.O’C.), University of California, San Diego, and Veteran’s Affairs San Diego Healthcare System (D.T.O., S.K.M.), La Jolla, California 92093-0838

Address all correspondence and requests for reprints to: Sushil K. Mahata, Ph.D., Department of Medicine (0838), University of California, San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System, 9500 Gilman Drive, La Jolla, California 92093-0838. E-mail: smahata{at}ucsd.edu.

The plasma level of chromogranin A (CgA) is elevated in genetic hypertension. Conversely, the plasma level of the CgA peptide catestatin is diminished in individuals with established hypertension and those with a genetic risk of this disease. Resequencing of the human CHGA gene identified three naturally occurring variants of catestatin (Gly364Ser, Pro370Leu, and Arg374Gln) that exhibit different potencies in inhibiting catecholamine secretion. Here, we have examined whether there is any differential processing of the three CHGA variants to catestatin by the endoproteolytic enzyme plasmin. Plasmin digestion of the purified CgA proteins generated a stable biologically active 14-amino acid peptide (human CgA_360–373) from the wild-type, Gly364Ser, and Arg374Gln proteins despite the disruption of the dibasic site (Arg₃₇₃Arg₃₇₄) in the Arg374Gln variant. Unexpectedly, the action of plasmin in generating the catestatin peptide from the Pro370Leu protein was less efficient. The efficiency of cleavage at the dibasic Arg₃₇₃Arg₃₇₄ site in synthetic human CgA_360–380 was 3- to 4-fold less in Pro370Leu CgA, compared with the wild type. Circular dichroism of the synthetic CgA_352–372 suggested a difference in the amount of -helix and β-sheet between the wild-type and Pro370Leu CgA peptides. Because the Pro₃₇₀ residue is in the P4 position, the local secondary structure in the vicinity of the cleavage site may enforce the specificity or accessibility to plasmin. The less efficient proteolytic processing of the Pro370Leu protein by plasmin, coupled with the strong association of this variant with ethnicity, suggests that the Pro370Leu CHGA gene variant may contribute to the differential prevalence of cardiovascular disease across ethnic groups.

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