1TEJ from Echis Carinatus:
A Heterodimeric Disintegrin Protein
Kit Ross '24 and Zion Snardon '23
Contents:
I. Introduction
As
a disintegrin,
1TEJ
is a transmembrane protein that binds to and antagonizes
cell-surface proteins known as integrins. Integrins are important
for blood clotting, which is why the disintegrin-containing
venom of E. carinatus is deadly. However,
integrins are
also involved in promoting the invasion of tumors, giving
disintegrins
interesting potential applications as therapeutics. A conserved
region among disintegrins
called the Arg-Gly-Asp
loop is known to be the site where the protein interacts with integrins.
1TEJ
contains two of these loops, one in each chain, and is thereby
uniquely able to inhibit two integrin
proteins at once.
II. General Structure
1TEJ
is a heterodimer composed of
each containing 64 amino acids. The total protein is therefore 128
amino acids long and it has a molecular weight of 14.08 kDa. The
heterodimeric structure of 1TEJ
is composed of two very similar but distinct monomers. Because
the 1TEJ
monomers are attached at their
, the molecule shows a distinct polarity and asymmetry. The
two monomers are held together by
one between Cys 12 (Chain A)
& Cys 7 (Chain B)
and the other between Cys 7 (Chain A)
& Cys 12 (Chain B).
In addition to these crossed disulfide bonds, there is also hydrogen
bonding in the Asn 4 of either chain.
The A Chain
contains three pairs of hydrogen bonded, antiparallel
. The B Chain
only contains two. Beta sheets have important structural roles in
enzymes and proteins because they are able to make many hydrogen
bonds to one another to form beta pleats and beta sheets. The
asymmetry of Chain A
and Chain B
has a significant effect on its binding because Chain B
is more flexible than Chain A.
III. Integrin Binding
Integrins
are transmembrane proteins that process outside stimuli and
communicate with the ECM and can help cell growth, adhesion,
communication, etc. They are heterodimeric proteins with two
distinct binding sites: the alpha (a) and beta (b). Our
disintegrin
has specifically high affinity when binding to aIIb3 or
avb3 integrins.
These two types of integrins
are able to recognize conserved Arg-Gly-Asp
loops in proteins that our body makes such as fibronectin and
lamina, but also they recognize the Arg-Gly-Asp
loops of disintegrins
.
The main function of
disintegrins
is to bind and inhibit integrins
through the action of the conserved Arg-Gly-Asp
loop. 1TEJ has two of
located near the C-terminus ends of each of the chains.
The Arg-Gly-Asp
loops on each chain are identical, except for
the fact that the
on the A Chain
is facing the opposite direction as the one on the
B Chain.
The ability of this loop to bind integrins
depends on how it interacts with the nearby
of the chain. The proximity of these two areas of the
protein brings many
together that create patches of polarity that promote the
binding of integrins.
IV. Integrin Specificity and Targeting
Although the Arg-Gly-Asp
loop is conserved among distintegins, different disintegrins
are able to target different types of integrins.
Slight differences in the shape and arrangement of the Arg-Gly-Asp
loop rather than sequence differences are thought to cause
differing integrin
specificity among
disintegrin.
For example, the
of the Arg-Gly-Asp
loop can be in an extended or narrow conformation, which enable
the loop to interact with aIIb3 or avb3, respectively. Because 1TEJ
is a heterodimer, the A Chain
and B Chain
have slightly
of the Gly residue in each of their Arg-Gly-Asp
loops that remarkably allows for the binding of both types of integrins.
V. References
D
A Warrell, Davidson NMcD, B M Greenwood, L D Ormerod, H
M Pope, B J Watkins, C R Prentice. Poisoning by bites of
the saw-scaled or carpet viper (Echis carinatus) in
Nigeria. National Library of Medicine. 1977 Jan;
46(181):33-62.
Iain
D. Campbell and Martin J.
Humphries. Integrin Structure,
Activation, and Interactions.
Cold Spring Harb Perspect
Biol. 2011 Mar; 3(3):
a004994. doi:
10.1101/cshperspect.a004994.
Gunasekera,
James S
Nowick. Exploring beta-sheet structure and
interactions with chemical model systems. National
Library of Medicine. 2008 Oct; 41(10):1319-30.
doi: 10.1021/ar800064f. Epub 2008 Sep 18.
Sameeta
Bilgrami, Savita Yadav, Punit Kaur, Sujata Sharma,
Markus Perbandt, Christian Betzel, and Tej P. Singh.
Crystal Structure of the Disintegrin Heterodimer from
Saw-Scaled Viper (Echis carinatus) at 1.9 A
Resolution. Biochemistry. 2005; 44 (33):
11058-11066. doi: 10.1021/bi050849y.
Sameeta Bilgrami, Shailly Tomar, Savita
Yadav, Punit Kaur, Janesh Kumar, Talat Jabeen, Sujata Sharma
and Tej P. Singh. Crystal Structure of Schistatin, a
Disintegrin Homodimer from Saw-scaled Viper (Echis carinatus)
at 2.5 A Resolution. Journal of Molecular Biology.
2004; 341(3): 829-837. doi: 10.1016/j.jmb.2004.06.048.
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