Here normal MI values are displayed for all pairs of secondary structural elements and loop regions , and all pairs of subdomains . The robust co evolutionary residence of residues in the subdomain IIB is clearly observed from panel b, succeeded by that within subdomain IB. Between the intersubdomain correlations, we distinguish the pair of subdomains IB and IIB. Consistent with these patterns, 4 groups of secondary structural aspects are distinguished in panel a by their most correlated evolutions: sheet E and connecting loop in subdomain IIB, the b strand R100 Y107, and loop in between helices 1 and 2 in subdomain IB, and also a b strand and preceding flip in subdomain IA. Figure 6d describes in extra detail the co evolutionary properties inside the subdomain IIB. The bar plots along the upper abscissa indicate the common MI values corresponding to each and every residue. The residues involved in NEF recognition are colored from the Hsp70 ATPase domain subdomain to which they belong. We note in particular the remarkably large MI values corresponding towards the pairs of residues inside the b sheet E, except to the discontinuity on the loop residue G290.
In addition, these residues display remarkably large co evolutionary patterns with amino acids on helix 9 . Examples of such tremendously correlated pairs are R258 Y288, T265 D285 and T273 Y288 . Notably, helix Vandetanib selleck chemicals 9 also has remarkably conserved residues concerned in nucleotide binding. This blend of co evolving and conserved residues endows helix 9 by using a completely unique mediating role involving the NEF binding area as well as the nucleotide binding pocket. Notably, the two b strands and preceding a helix on subdomain IIB emerge being a co evolved structural entity, distinguished by its NEF recognition and binding role, reminiscent in the practical ?sectors? pointed out by Ranganathan and coworkers for S1A serine proteases. Figure 6c reveals the cross correlations among the evolutionary trends of subdomain IIB residues plus the residues 16 75 on subdomains IA and IB. The above mentioned residues of subdomain IIB seem to get co evolved with welldefined residues on subdomains IA and IB.
Particularly the pairs E27 R258, E27 Y288, Q33 T273 and Q33 E283, exhibit remarkably substantial correlations , in spite of their lengthy distance separation over the structure. The observed sequence correlations could arise from many causes together with those originating in the splits among subfamilies . Particularly, subdomain IIB has phylogenetic background contributing Nilotinib to its high variability, and subfamilies have evolved to companion with numerous NEFs. Regardless on the origin of these correlations, the MI map unambiguously shows that NEF binding residues are distinguished by their co evolutionary properties.