Burge, C. way to increase the efficiency of protein design and to engineer complex functionality such as interaction specificity. and protein Dscam16 (Fig. 1). Dscam represents a particularly interesting case from an evolutionary perspective. Dscam consists of 10 immunoglobulin-like domains, three of which are variable and play important roles in homodimerization. Each of these three variable domains is encoded by an exon block, and mutually exclusive splicing at each block gives rise to more than 10,000 distinct isoforms. It was shown that each variable domain is largely specific for interaction with itself, and the combined action of the three domains results in high binding specificity of the full-length Dscam,16 a key property for neurons to distinguish self from nonself (self-avoidance) in development. Evolutionary analysis suggested that each exon block was evolved by exon duplication followed by sequence divergence,17 illustrating how selective pressure exerted by the need to maintain self-avoidance can help shape the remarkable homo-specificity of the Dscam family. Open in a separate window Figure 1 Examples of different types of proteinCprotein interactions where the protein fold is conserved but the specificity can be varied. A representative complex is shown for each class of interaction: A: Complex between SH3 domain from the Abl tyrosine kinase (green) and a proline-rich peptide (red). (PDB ID: 1ABO).169 B: Complex between SH2 domain from the SAP protein (green) and a phosphotyrosine peptide (red) (PDB ID: 1D4W).170 C: Complex between Erbin PDZ domain (green) and the C-terminal tail of the ErbB2 receptor (red) (PDB ID: 1MFG).171 D: Complex between the bZIP coiled-coil motifs of FOS (green) and JUN (red) (PDB ID: 1FOS).172 E: Complex between anti-apoptotic protein Mcl-1 (green) and the BH3 region of Bim (red) (PDB ID: 2PQK).173 F: Complex of a homodimer formed by the N-terminal domain of a particular Dscam isoform (PDB ID: 2V5M).174 Figure generated using PyMol (Delano Scientific). Interestingly, solved structures of proteins with similar sequences but distinct interactions have revealed that often the same binding interface is utilized, and differences in binding preferences can be attributed to local differences in structures.18C26 Some natural proteins share a similar protein NSC 131463 (DAMPA) fold yet differ in their interaction properties through use of different conformations for loops linking helices and/or strands that define a NSC 131463 (DAMPA) basic scaffold. A good example is the SH2 family, which interacts with peptides that contain a phosphorylated tyrosine (pTyr).11,12 Specificity of SH2 domains interacting with different pTyr peptides is crucial for correctly transmitting signals from protein tyrosine kinases to downstream pathways. Three main classes of SH2 domains recognize peptides with different sequence signatures C-terminal to pTyr. Loops flanking the binding interface confer selectivity toward these 3 types of peptides by opening NSC 131463 (DAMPA) or blocking binding pockets for the P+2, P+3 or P+4 residues.19,20 The SH3 family also utilizes different loop conformations at the binding interface to provide specificity toward different peptides that are rich in prolines.19 Antibodies provide another example of using loops to confer different binding properties,23 sharing a common immunoglobulin scaffold but using variation in 6 surface loops, the complementarity-determining regions (CDR), to achieve exquisite specificities for antigens. NSC 131463 (DAMPA) Although changes in local structures such as loops present a convenient way to change interaction properties, examples of more subtle sequence/structural features providing specificity abound in nature as well. One example is the interaction between colicin endonucleases (DNases) and immunity (Im) proteins. Colicins are Mouse monoclonal to CD49d.K49 reacts with a-4 integrin chain, which is expressed as a heterodimer with either of b1 (CD29) or b7. The a4b1 integrin (VLA-4) is present on lymphocytes, monocytes, thymocytes, NK cells, dendritic cells, erythroblastic precursor but absent on normal red blood cells, platelets and neutrophils. The a4b1 integrin mediated binding to VCAM-1 (CD106) and the CS-1 region of fibronectin. CD49d is involved in multiple inflammatory responses through the regulation of lymphocyte migration and T cell activation; CD49d also is essential for the differentiation and traffic of hematopoietic stem cells stress-induced bacterial bacteriocins. Toxicity of colicins against their own producing cells is neutralized by interaction with cognate Im proteins, so high interaction specificity is critical. A crystal structure of a noncognate complex between DNase ColE9 and Im2 was NSC 131463 (DAMPA) solved recently and comparison was made to the structure of the cognate complex between DNase ColE9 and Im9.24 The backbone and side-chain packing at the core of the two interfaces was highly similar. However, the presence of unfavorable polar/charged residue burial and suboptimal hydrogen bonding patterns weakened interaction significantly for the noncognate complex. For bZIP coiled.

Related Posts