Anchor residues

Scott, C.A., Peterson. P.A., Teyton, L., Wilson, LA. Crystal structures of two 1-A -peptide complexes reveal that high affinity can be achieved without large anchor residues. Immunity 8 319-329, 1998. 

OSN responses to peptides were found to be highly sensitive, with thresholds down to 10 11M, although they were around two orders of magnitude less sensitive than VSN responses (Spehr et al. 2006). OSN responses to MHC peptide ligands also displayed a different dependence on anchor residues. Whereas replacement of anchor residues with alanines abolished the responses of VSNs, it shifted the stimulus response curve of around two thirds of the OSNs, making them less sensitive by approximately two orders of magnitude. However, OSNs still failed to respond to the scrambled version of the peptide or a mixture of its constituent amino acids (Spehr... 

Two distinct structural elements play a role in the ubiquitination of a target protein (i) the E3 recognition site and (ii) the anchoring residue of the polyubiquitin chain. In most cases, it is believed, though it has been shown for only a few proteins, that the first ubiquitin moiety is transferred to an -NH2 group of an internal lysine residue in the substrate. The N-terminal domain of the target protein has attracted attention both as an E3 recognition domain and, recently, as a ubiquitination site. 

Figure 6b shows the modeled a helix F interface in human 17P-hydroxysteroid dehydrogenase type 2. Alanine-237 is 3 A from the hydrophobic part of the side chain of methionine-241 on the other subunit. Methionine-241 is 3.2 A from serine-234. Alanine-230 is 3.7 A from phenylalanine-242 and 4.5 A from valine-245. Alanine-238, the other anchoring residue, is 4.1 A from alanine-238 on the other subunit. 

Rajamani D, Thiel S, Vajda S, Camacho CJ. Anchor residues in protein-protein interactions. Proc. Natl. Acad. Sci. U.S.A. 2004 101 11287-11292. 

The groove can be filled by a peptide from 8 to 10 residues long in an extended conformation. As we shall see (Section 33.5.6). MHC proteins are remarkably diverse in the human population each person expresses as many as six distinct class I MHC proteins and many different forms are present in different people. The first structure determined, HLA-A2, binds peptides that almost always have leucine in the second position and valine in the last position (Figure 33.25). Side chains from the MHC molecule interact with the amino and carboxyl termini and with the side chains in these two key positions. These residues are often referred to as the anchor residues. The other residues are highly variable. Thus, many millions of different peptides can be presented by this particular class I MHC protein the identities of only two of the nine residues are crucial for binding. Each class of MHC molecules requires a unique set of anchor residues. Thus, a tremendous range of peptides can be presented by these molecules. Note that one face of the bound peptide is exposed to solution where it can be examined by other molecules, particularly T-cell receptors. An additional remarkable feature of MHC-peptide complexes is their kinetic stability once bound, a peptide is not released, even over a period of days. 

Figure 33.25. Anchor Residues. (A) The amino acid sequences of three peptides that bind to the class I MHC protein HLA-A2 are shown. Each of these peptides has leucine in the second position and valine in the carboxyl-terminal position. (B) Comparison of the structures of these peptides reveals that the amino and carboxyl termini as well as the side chains of the leucine and valine residues are in essentially the same position in each peptide, whereas the remainder of the structures are quite different.

Rovero, R, Riganelli, D., Fruci, D., Vigano, S., Pegoraro, S., Revoltella, R., Greco, G., Butler, R., dementi, S. and Tanigaki, N. (1994). The Importance of Secondary Anchor Residue Motifs of HLA Class I Proteins A Chemometric Approach. Mol.Immunol., 31,549-554. 

The rules for peptide selection by MHC class I molecules were defined by the characterization of peptide mixtures extracted from class I complexes [33], and furthermore, by the effects of collections of different peptides on binding to MHC molecules and by the response of cytotoxic T cells on these presented peptides [34]. Crystal structure analyses of defined MHC-peptide and MHC-peptide-T-cell receptor (TCR) complexes [35-38] gave detailed information on the molecular interaction between peptides and MHC proteins. MHC class I ligands are mainly octa- or nonapeptides and obey allele-specific sequence motifs carrying prominent anchor residues [24], The peptide-binding groove offers specific pockets to interact with these anchor residues [35]. 

Prominent primary anchor residues in anchor positions determined by pool sequencing (e.g., positions 5 and 8 for H-2Kb, positions 2 and 8 for H-2Ld) were ascertained by screening octapeptide libraries [39], Unfavorable effects on binding can be induced also by amino acids in non anchor positions. Conformational analysis of several individual peptides bound to MHC class I molecules showed that the position of the peptide backbone in the binding groove, as well as the orientation of side chains in other sequence positions, is influenced by individual amino acid side chains [36]. These interactions strongly determine the accessibility of the peptide on the MHC 1 surface and thus the response of the CTL effector cells. Anchor residues promote efficient binding to MHC 1, but notably suppress the CTL response to the complex peptide libraries [39]. 

As indicated by AI and AJ, the carboxylic side of the metal-bearing residue is cleaved with short peptide substrates. With longer peptides and proteins, the Pd(ll) reagents cleaved peptide bonds located on the amino side of the Pd(ll)-anchoring residue as indicated by AK (97). 

The interspersed non-anchor residues are candidates for recognition by TcR, with the precise choice of residues determining the TcR specificity. The stability of MHC Il-peptide complexes and, thus, the composition of the set of peptides actually available for T cell activation, is not simply defined by the sum of anchor residue-specific incremental energies but also by the combination of anchor residues and side chains at non-anchor positions e.g., proline, glycine. 

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