| Literature References | 1. BODE, W., MAYR, I., BAUMANN, U., HUBER, R., STONE, S.R. AND HOFSTEENGE, J.
The refined 1.9A crystal structure of human alpha-thrombin: interaction with
D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp
insertion segment.
EMBO J. 8 3467-3475 (1989).
2. GUINTO, E.R., CACCIA, S., ROSE, T., FUETTERER, K., WAKSMAN, G.
AND DI CERA, E.
Unexpected crucial role of residue 225 in serine proteases.
PROC.NATL.ACAD.SCI.U.S.A. 96 1852-1857 (1999).
3. BANFIELD, D.K. AND MACGILLIVRAY, R.T.
Partial characterization of vertebrate prothrombin cDNAs: amplification and
sequence analysis of the B chain of thrombin from nine different species.
PROC.NATL.ACAD.SCI.U.S.A. 89 2779-2783 (1992).
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| Documentation | The amino acid sequence of prothrombin has a modular architecture,
comprising a series of N-terminal gamma-carboxyglutamate residues,
activation peptides 1 and 2, thrombin light chains A and B, and two kringle
domains. Modification of the glutamyl residues is necessary for calcium-
dependent interaction of the protein with a negatively charged phospholipid
surface, which is essential for the conversion of prothrombin to thrombin.
Prothrombin activation at the membrane surface is mediated by factors Va
and Xa. Factor Xa removes the activation peptide and cleaves the remaining
part into light and heavy chains. Activation is slow because factor V
itself has to be activated by the initial small amounts of thrombin.
Thrombin is a member of the trypsin family of S1 peptidases. It catalyses
the preferential cleavage of arginine-lysine bonds, converting fibrinogen
to fibrin, and releasing fibrinopeptides A and B. Thrombin can itself cleave
the N-terminal fragment (fragment 1) of prothrombin, prior to its activation
by factor Xa. Its effects are mediated by the thrombin receptor.
The structure of the thrombin A-chain has been determined to 1.9A resolution
[1]. The A-chain, which is ordered only in its central part, is positioned
along the molecular surface opposite to the active site. The B-chain
exhibits the characteristic fold of trypsin-like proteases [1,2].
The most conserved portions of the B chain are the active-site residues and
adjacent amino acids, the B loop, and the primary substrate-binding region
[3]. The regions of poorest conservation in the B chain correspond to
surface loops, including putative thrombomodulin-binding sites and a
hirudin-binding region. The extent of sequence similarity between species
and the conservation of many of the functional/structural motifs suggests
that, in addition to their role in blood coagulation, vertebrate thrombins
may play an important role in the general mechanisms of wound repair [3].
PROTHROMBIN is an 4-element fingerprint that provides a signature for
prothrombin. The fingerprint was derived from an initial alignment of 4
sequences: the motifs were drawn from conserved regions spanning the
C-terminal two-thirds of the alignment - motif 1 encodes the C-terminal
alpha-helix of the thrombin light chain (A); and motifs 2-4 span the
thrombin heavy chain (B) - motif 2 encodes helices 2 and 3 and strands 6 and
7; motif 3 encodes strand 10; and motif 4 spans strand 15 and helices 6 and
7. A single iteration on SPTR37_10f was required to reach convergence, no
further sequences being identified beyond the starting set. A single partial
match was found,
An update on SPTR57.15_40.15f identified a true set of 21 sequences, and two
partial matches (Q90504_EPTST and B3XZZ0_LAMJA), which are pacific hagfish
and Japanese lamprey thrombins that fail to match motif 1.
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