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  • Title: The shape of high molecular weight kininogen. Organization into structural domains, changes with activation, and interactions with prekallikrein, as determined by electron microscopy.
    Author: Weisel JW, Nagaswami C, Woodhead JL, DeLa Cadena RA, Page JD, Colman RW.
    Journal: J Biol Chem; 1994 Apr 01; 269(13):10100-6. PubMed ID: 8144509.
    Abstract:
    Knowledge of the organization of the kininogen gene and protein structure and function correlations has allowed the development of a model of high molecular weight kininogen. Domains 1-3 on the heavy chain are evolutionarily related to cystatin and the latter two are inhibitors of cysteine proteases. Proteolytic cleavage in domain 4 to release bradykinin causes a conformational change, exposing a surface-binding region (domain 5) on the disulfide-linked light chain. The carboxyl-terminal domain 6 contains a zymogen binding sequence for factor XI and prekallikrein which, with domain 5, accounts for its cofactor activity. To explore further the domain structure, we have determined the shapes of high molecular weight kininogen and prekallikrein by electron microscopy of rotary shadowed preparations and computer image processing. High molecular weight kininogen appears to be a linear array of three linked globular regions about 16 nm long, with the two ends also connected by another thin strand. Both prekallikrein and kallikrein have a compact globular shape, with a subdivision that is sometimes visible. Different functional domains of high molecular weight kininogen were identified by monoclonal antibodies against these regions, as well as ligand binding of prekallikrein. These studies indicate that one end globular region is the prekallikrein-binding domain, the other comprises the cysteine protease inhibitor domains and the smaller central nodule is the surface-binding domain. Cleavage of high molecular weight kininogen with plasma kallikrein to yield two-chain high molecular weight kininogen results in a striking change in conformation: the central surface-binding domain swings out so that it is still adjacent to the prekallikrein-binding domain but no longer in the middle. These structural studies provide insight into the interactions of these proteins and aspects of the mechanisms of their actions.
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