Conformational Determinants of Phosphotyrosine Peptides Complexed with the Src SH2 Domain

The inhibition of specific SH2 domain mediated protein-protein interactions as an effective chemotherapeutic approach in the treatment of diseases remains a challenge. That different conformations of peptide-ligands are preferred by different SH2 domains is an underappreciated observation from the structural analysis of phosphotyrosine peptide binding to SH2 domains that may aid in future drug design. To explore the nature of ligand binding, we use simulated annealing (SA) to sample the conformational space of phosphotyrosine-containing peptides complexed with the Src SH2 domain. While in good agreement with the crystallographic and NMR studies of high-affinity phosphopeptide-SH2 domain complexes, the results suggest that the structural basis for phopsphopeptide- Src SH2 interactions is more complex than the “two-pronged plug two-hole socket” model. A systematic study of peptides of type pYEEX, where pY is phosphotyrosine and X is a hydrophobic residue, indicates that these peptides can assume two conformations, one extended and one helical, representing the balance between the interaction of residue X with the hydrophobic hole on the surface of the Src SH2 domain, and its contribution to the inherent tendency of the two glutamic acids to form an α-helix. In contrast, a β-turn conformation, almost identical to that observed in the crystal structure of pYVNV bound to the Grb2 SH2 domain, predominates for pYXNX peptides, even in the presence of isoleucine at the third position. While peptide binding affinities, as measured by fluorescence polarization, correlate with the relative proportion of extended peptide conformation, these results suggest a model where all three residues C-terminal to the phosphotyrosine determine the conformation of the bound phosphopeptide. The information obtained in this work can be used in the design of specific SH2 domain inhibitors

Ecosystem services from smallholder forestry and agroforestry in the tropics

Smallholder forestry and agroforestry systems in the tropics provide essential products and services for millions of producers, their surrounding communities, national and international consumers, and global society. The diversity of products provided by these systems meet the needs of smallholder producers for fuelwood, food, animal fodder, and other household and farm needs; they provide additional income to supplement major commodity crops; and they offer flexibility in production and income to buffer against falling commodity prices, crop failure, or other sources of financial or economic difficulty. The sustainability of these systems is increasingly dependent upon sources of income beyond the sale of conventional products, such as price premiums from sustainability certification and agro- and ecotourism. Payments for ecosystem services (PES) programs have been developed at multiple levels to provide incentives for smallholders to conserve and enhance tree cover and management practices to provide ecosystem services such as watershed protection and carbon sequestration. Ecotourism provides an enterprise-based strategy to engage producers in conservation and enhancement of these services. This review evaluates the ability of smallholder systems to support the provision of ecosystem services (ES) and the capacity of smallholders to participate in support programs and take advantage of other emerging opportunities to support smallholder enterprises