Kringle Domains

Figure 2.19 Organization of polypeptide chains into domains. Small protein molecules like the epidermal growth factor, EGF, comprise only one domain. Others, like the serine proteinase chymotrypsin, are arranged in two domains that are required to form a functional unit (see Chapter 11). Many of the proteins that are involved in blood coagulation and fibrinolysis, such as urokinase, factor IX, and plasminogen, have long polypeptide chains that comprise different combinations of domains homologous to EGF and serine proteinases and, in addition, calcium-binding domains and Kringle domains.

Kringle domains, which have a characteristic pattern of three internal disulfide bridges within a region of about 85 amino acid residues. 

FIGURE 6.38 A sampling of proteins that consist of mosaics of individual protein modules. The modules shown include 7CG, a module containing 7-carboxyglutamate residues G, an epidermal growth-factor-like module K, the kringle domain, named for a Danish pastry ... 

NK4 (4-kringle domains of HGF) Inhibits EC differentiation and migration induced by VEGF... 

Kinase Domain Kinase Inhibitors Kinins Kir Channels Knockout Mice Kringle Domains K+-Sparing Diuretics Kv(3 -Subunits Kv-Channels KvLQT 1 -Channels Kynurenine Pathway L-NAME... 

Gehrmann, M., Briknarova, K., Banyai, L., Patthy, L., and Llinas, M. (2002). The col-1 module of human matrix metalloproteinase-2 (MMP-2) Structural/functional relatedness between gelatin-binding fibronectin type II modules and lysine-binding kringle domains. Biol. Chem. 383, 137-148. 

A structural domain consists of 100-150 residues in various combinations of motifs. Often a domain is characterized by some interesting structural feature an unusual abundance of a particular amino acid (e.g., a prollne-rich domain, an acidic domain), sequences common to (conserved in) many proteins (e.g., SH3, or Src homology region 3), or a particular secondary-structure motif (e.g., zinc-finger motif in the kringle domain). 

Proposed features of the interaction between the prothrombinase complex and a membrane lipid bilayer.Ky and K2 are the kringle domains of prothrombin, and EGFl and EGF2 are the two epidermal growth factor units of factor X. Prothrombin and factor form a heterodimer complex harbored within the membrane protein factor Va- The proposed interaction between prothrombin and factor X involves hydrophobic interactions between two helices and bridging by a ion between two Gla residues. The N-terminal Gla residues attach the heterodimer complex to the phospholipid surface. Figure kindly provided by C. C. F. Blake. 

The Gla-containing proteins of the blood coagulation system are all modular with the Gla-domain N terminal. Factors VII, IX, and X and protein C form a group with the same domain structure. The Gla domain is followed by two EGF-like domains, of which the first one also binds calcium (see Section IV.C), and a serine protease domain, also with a calcium-binding site (see Section IV.D). Prothrombin and protein S have somewhat different domain structures (145, 146). In prothrombin the Gla domain is followed by a hexapeptide with a disulfide loop, two kringle domains, and the C-terminal serine protease domain. In protein S the Gla domain is followed by the thrombin-sensitive loop, four EGF-like domains, and the C-terminal domain that is homologous to plasma steroid hormone-binding proteins. 

It remains unclear whether such approaches are truly general, in particular for proteins such as receptors that span different cellular compartments. For example, some receptor tyrosine kinases contain a kringle domain in their extracellular regions. Would such protocols predict common functions for intracellular tyrosine kinases and extracellular kringle-containing proteins, such as those of the hlood coagulation pathway Nevertheless, it is apparent that considerable functional constraints exist for domains to co-occur and that domain combinations are often very limited. 

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