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A notable distinction from a typical Fab
fragment structure lies in the relative orientation of the four
TCR domains. The TCR molecule appears vertically compressed, with
a shorter length and increased width compared to related antibody
structures. This squat appearance is determined largely at the
interdomain pairings.
The interface of the variable and constant
domains is extensive, with much greater buried surface area than
seen in immunoglobulin VH-CH1 or VL-CL
interfaces. This elbow region of the molecule is dominated by
interactions within the beta chain. While the contact between
alpha chain variable and constant regions is smaller and limited
to hydrophobic residues, the Vβ-Cβ interaction is marked by a highly polar region and a
conserved salt bridge (Arg113-Glu158β).
The Vβ-Cβ interface contains a common "ball and socket"
joint conserved in the VH-CH1 interface of
immunoglobulins. This joint, formed by a phenylalanine (ball) and
serine, valine, and leucine residues (socket), may allow some
rotational flexibility in the elbow angle of the TCR. This
suggests a possible conformational change upon ligand binding,
and supports the idea of a TCR momomer directing intracellular
signalling. The highly polar interface and conserved salt bridge,
however, seem to indicate otherwise, and support the hypothesis
of a rigid TCR forming aggregate multimers to initiate the
activation signal.
In addition to the inter-chain disulphide bond,
there is considerable complementarity between the alpha and beta
chain constant regions. The interface is marked by an asymmetric
distribution of charged residues, with the alpha chain bearing a
net negative charge and the beta chain marked by a predominance
of positively-charged basic residues. Within this generalized
electrostatic attraction are two conserved salt bridges between
the Cα
and Cβ
domains (Glu122α-Lys140β and
Asp145α-Arg197β), and an interesting water-mediated hydrogen bond
(Thr139α-HOH-Arg150β).
Much like the immunoglobulin CH3-CH3
interface, the TCR Cα-Cβ
interface is stabilized by a carbohydrate linkage.
Unlike immunoglobulins, however, the sugar attachment for the TCR
is asymmetric, and it occurs at the outer edge of the interdomain
pairing. A fucose ring on a carbohydrate moiety extending from
Asn185α
is hydrogen bonded to the side-chain oxygens of
Glu181β and
Ser182β. This indicates a
critical role of post-translational glycosylation in stabilizing
the quarternary structure of multimeric proteins.
The Vα-Vβ interface is marked by a
symmetric pairing of polar and hydrophobic residues. The contact
area between the two variable domains is small compared to that
seen in most antibody Fab fragments. The decreased contact area
coupled with the lack of fixed salt bridges seems to indicate a
possible conformational change upon antigen binding. This is
analogous to the ability of certain Fab fragments to alter their
domain associations to achieve better shape complementarity when
bound to antigen.
