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Structural Insights into Fibrinogen Dynamics Using Amide Hydrogen/Deuterium Exchange Mass Spectrometry


Fibrinogen is a large, elongated, tri-globular plasma protein that serves as the precursor of the fibrin clot. Fibrinogen consists of two identical disulfide-linked subunits, each containing three non-identical polypeptide chains, A[alpha], B[beta], and [gamma]. The amide hydrogen /deuterium exchange profile of native human fibrinogen has been determined under physiologic conditions. After optimization of the quench and proteolysis conditions, more than 1,200 peptides were identified by mass spectrometry spanning more than 90% of the constituent A[alpha], B[beta], and [gamma] chain amino acid sequences. The compact central and distal globular regions of fibrinogen were well-protected from deuterium exchange, with the exception of the unfolded amino-terminal segments of the A[alpha] and B[beta] chains extending from the central region and the short [gamma] chain "tail" extending from each distal globular region. The triple- helical coiled-coil region, which bridges the central region to each distal region, was also well protected with the exception of a moderately fast-exchanging area in the middle of the coiled coil adjacent to the [gamma] chain carbohydrate attachment site. This dynamic region likely represents the "hinge" that provides flexibility to the fibrinogen molecule. The segment corresponding to the [gamma] chain "out loop" also exchanged rapidly. The [alpha]C domain (A[alpha] 392-601), whose structure has been a matter of considerable debate, exchanged rapidly, with the exception of a short segment sandwiched between a conserved disulfide linkage in the N-terminal [alpha]C subdomain. These findings are consistent with a mostly disordered structure for the [alpha]C domain in native fibrinogen

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