Kringle region

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

The four common motifs found within the amino terminal regions of the proteinase precursors and proteinases are kringles, epidermal growth factor (EGF)-like motifs, fibronectin motifs, and apple motifs (Figure 36-5). The kringle is so named because in two dimensions, i.e., on paper prior to determination of its three-dimensional structure, it has the shape of a Danish pretzel. Similarly, apple motifs resemble drawings of apples. 

CHAPTER 36, FIGURE 5 Motif structures within coagulation proteins. Common motifs are found in the amino terminal regions of the proteinase precursor molecules. Shown are the kringle motifs and EGF-like motifs found in the vitamin K-dependent proteins and in plasminogen. Fibronectin (types I and II) motifs and apple motifs (named from their two-dimensional representations) are also present but not shown. Some epidermal growth factor-like domains contain P-hydroxylated Asp residues. The cartoon structures for the motifs are derived from three-dimensional structures determined by x-ray crystallography or by two-dimensional NMR spectroscopy. 

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). 

Fig. 6. A model of lipoprotein(a) assembly. Lipoprotein(a) assembly proceeds through a two-step model in which an initial non-covalent interaction between apo(a) and apo B precedes specific disulfide bond formation. The initial non-covalent interaction is mediated by interaction between two lysine residues (K and K ) within the N-terminal 18% of apo BlOO and the weak lysine-binding sites (LBS) in apo(a) kringle IV types 7 and 8. A disulfide bond is subsequently formed between a cysteine in the C-terminal region of apo BlOO and apo(a). The types of kringle IV are indicated by boxed numbers. From Dr. J.P. Segrest, University of Alabama at Birmingham Medical Center, with premission.

LDLs and apo(a) have been secreted. Initially, two lysine residues (Lys-680 and Lys-690) in the N-terminal 18% of apo BlOO interact non-covalently with a lysine-binding site in apo(a) (Fig. 6) (M.L. Koschinsky, 2001). Next, the C-terminal region of apo BlOO interacts non-covalently with amino acids 4330-4397 of apo(a), and a disulfide bond is subsequently formed between apo BlOO and apo(a). The kringle-4 domain of apo(a) can be present in a variable number of copies (3 to >40), resulting in size heterogeneity of lipoprotein(a). Generally, the plasma level of lipoprotein(a) is inversely correlated with apo(a) isoform size (i.e., the number of kringles). An inverse relationship has also been observed between apo(a) isoform size and the efficiency of covalent association of apo(a) with apo B. Consequently, it has been proposed that this relationship contributes to the inverse correlation between apo(a) isoform size and plasma lipoprotein(a) levels [22]. 

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. 

Gla region, Kringle 1 is encoded by exons 5 and 6 while kringle 2 is encoded by exon 7, The thrombin portion of the protein is then encoded by exons 8 to 14. The other exons encode connecting peptides. The organization of these regions of the prothrombin... 

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