Variable region conservation

A sequence alignment establishes the correspondences between the amino adds in th unknown protein and the template protein (or proteins) from wliich it will be built. Th three-dimensional structures of two or more related proteins are conveniently divided int structurally conserved regions (SCRs) and structurally variable regions (SVRs). Ihe structural conserved regions correspond to those stretches of maximum sequence identity or sequenc... 

List of Abbreviations GPCRs, G-protein coupled receptors PDB, protein database SCRs, structurally conserved regions SVRs, structurally variable regions... 

The R-Smad proteins interact with type I receptor and co-regulatory Smad (co-Smad) proteins in the signal cascade by virtue of conserved MH1 and MH2 domains at their N- and C-termini, which are separated by a variable, non-conserved region. These domains possess DNA binding and transcriptional activation functions, respectively. The inactive MH1 domain interacts with the MH2 domain in an auto-inhibitory manner. However, once C-terminal phosphorylation by the type I receptor occurs, this inhibitory association is alleviated and the R-Smad is then able to interact with its appropriate co-Smad. The phosphorylated R-Smad/co-Smad complex is capable of translocation to the cell nucleus where, in coordination with nuclear factors, it is able to exert its transcriptional activation function. 

Correlation of conserved and variable regions with the three-dimensional structure (S9) shows that residues involved in catalysis and in intersubunit contacts are conserved to a much greater extent than others. It follows that the sequence of the catalytic domain with its greater proportion of active site and subunit contact residues is more highly conserved than the sequence of the NAD-binding domain despite the fact that the latter represents a highly conserved structure. 

To localize the RGD residues on the Ad penton base, a cryo-EM reconstruction was performed of adenovirus type 2 (Ad2) complexed with an RGD-specific Eab fragment from an mAb directed against the penton base (Stewart et al, 1997). This structural analysis revealed that the RGD regions are at the top of protrusions on the pentameric penton base protein. In addition, it was deduced from the diffuse nature of the Fab density that the RGD residues were in a structurally variable surface loop. Comparison of the knovra sequences of the penton base protein from various adenovirus serotypes suggested that type 12 adenovirus (Adl2) would have the least structurally variable RGD loop, as Ad 12 has 45 fewer residues in the variable region flanking the conserved RGD residues than are found in Ad2 (Chiu et al, 1999). 

The H chains are less conserved than the L chains and the carboxyl-terminal part of the H chain (He) is the most variable region of the toxin (Fig. 2) (Minton, 1995). This is consistent with the notions that the He domain is involved in binding to the nerve terminals and that different neurotoxins bind to different cognate receptors. On this basis it may be suggested that the receptor binding regions of TeTx and BoNTs are mainly located within the 180 carboxy-terminal residues of the H chain. 

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