fibrin and Metabolism--Inborn-Errors

Fibrinogen is a large, complex, fibrous glycoprotein with three pairs of polypeptide chains linked together by 29 disulfide bonds. It is 45 nm in length, with globular domains at each end and in the middle connected by alpha-helical coiled-coil rods. Both strongly and weakly bound calcium ions are important for maintenance of fibrinogen's structure and functions. The fibrinopeptides, which are in the central region, are cleaved by thrombin to convert soluble fibrinogen to insoluble fibrin polymer, via intermolecular interactions of the "knobs" exposed by fibrinopeptide removal with "holes" always exposed at the ends of the molecules. Fibrin monomers polymerize via these specific and tightly controlled binding interactions to make half-staggered oligomers that lengthen into protofibrils. The protofibrils aggregate laterally to make fibers, which then branch to yield a three-dimensional network-the fibrin clot-essential for hemostasis. X-ray crystallographic structures of portions of fibrinogen have provided some details on how these interactions occur. Finally, the transglutaminase, Factor XIIIa, covalently binds specific glutamine residues in one fibrin molecule to lysine residues in another via isopeptide bonds, stabilizing the clot against mechanical, chemical, and proteolytic insults. The gene regulation of fibrinogen synthesis and its assembly into multichain complexes proceed via a series of well-defined steps. Alternate splicing of two of the chains yields common variant molecular isoforms. The mechanical properties of clots, which can be quite variable, are essential to fibrin's functions in hemostasis and wound healing. The fibrinolytic system, with the zymogen plasminogen binding to fibrin together with tissue-type plasminogen activator to promote activation to the active enzyme plasmin, results in digestion of fibrin at specific lysine residues. Fibrin(ogen) also specifically binds a variety of other proteins, including fibronectin, albumin, thrombospondin, von Willebrand factor, fibulin, fibroblast growth factor-2, vascular endothelial growth factor, and interleukin-1. Studies of naturally occurring dysfibrinogenemias and variant molecules have increased our understanding of fibrinogen's functions. Fibrinogen binds to activated alphaIIbbeta3 integrin on the platelet surface, forming bridges responsible for platelet aggregation in hemostasis, and also has important adhesive and inflammatory functions through specific interactions with other cell

Topics: Animals; Chemical Phenomena; Chemistry, Physical; Fibrin; Fibrinogen; Fibrinolysis; Humans; Metabolism, Inborn Errors; Protein Binding; Structure-Activity Relationship

Topics: Blood Protein Electrophoresis; Chronic Disease; Fibrin; Heterozygote; Homozygote; Humans; Leukocytes; Lysosomes; Metabolism, Inborn Errors; Methods; Protease Inhibitors; Protein Deficiency; Pulmonary Emphysema; Trypsin; Trypsin Inhibitors

Congenital disorders of glycosylation (CDG) comprise a family of inherited multisystemic disorders resulting from the deficiency of glycosylation pathways. N-glycosylation defects are classified as two biochemical and genetic established types, of which CDG-Ia is the most frequent. We performed 2-DE proteomic analysis on serum from two functional hemizygous CDG-Ia patients bearing T237M and D65Y missense changes. Comparative analysis of control/patient serum proteome allowed us to identify differential expression of 14 proteins. The most remarkable groups included proteins involved in immune response, coagulation mechanism and tissue protection against oxidative stress. The patient bearing D65Y mutation had less favourable clinical outcome and showed more abnormalities in the spot patterns, suggesting that the proteomic results might also be correlated with the phenotype of CDG patients. This study describes for the first time the differential expression of alpha(2)-macroglobulin, afamin, fibrin and fibrinogen in CDG disorder and shows how the proteomic approach might be useful for understanding its physiopathology.

Topics: alpha 1-Antitrypsin; alpha-Macroglobulins; Carrier Proteins; Child; Child, Preschool; Electrophoresis, Gel, Two-Dimensional; Female; Fibrin; Fibrinogen; Glycoproteins; Glycosylation; Humans; Isoelectric Focusing; Metabolism, Inborn Errors; Protein Biosynthesis; Proteins; Proteome; Proteomics; Serum; Serum Albumin; Serum Albumin, Human; Transferrin

Topics: Adult; Blood Coagulation; Female; Fibrin; Hemorrhagic Disorders; Humans; Metabolism, Inborn Errors; Plasma