A conserved residue in the P2X4 receptor has a nonconserved function in ATP recognition.

Highly conserved amino acids are generally anticipated to have similar functions across a protein superfamily, including that of the P2X ion channels, which are gated by extracellular ATP. However, whether and how these functions are conserved becomes less clear when neighboring amino acids are not conserved. Here, we investigate one such case, focused on the highly conserved residue from P2X4, E118 (rat P2X4 numbering, rP2X4), a P2X subtype associated with human neuropathic pain. When we compared the crystal structures of P2X4 with those of other P2X subtypes, including P2X3, P2X7, and AmP2X, we observed a slightly altered side-chain orientation of E118. We used protein chimeras, double-mutant cycle analysis, and molecular modeling to reveal that E118 forms specific contacts with amino acids in the "beak" region, which facilitates ATP binding to rP2X4. These contacts are not present in other subtypes because of sequence variance in the beak region, resulting in decoupling of this conserved residue from ATP recognition and/or channel gating of P2X receptors. Our study provides an example of a conserved residue with a specific role in functional proteins enabled by adjacent nonconserved residues. The unique role established by the E118-beak region contact provides a blueprint for the development of subtype-specific inhibitors of P2X4.

Cataract extraction surgery in patients with uveitis in Taiwan: risk factors and outcomes.

BACKGROUND/PURPOSE: To analyze the preoperative conditions and postoperative outcomes of phacoemulsification and intraocular lens implantation in Taiwanese patients with uveitis. METHODS: This retrospective, consecutive case series study included 121 eyes of 84 patients with uveitis who underwent phacoemulsification and intraocular lens implantation from July 1996 to May 2006. The demographic data, postoperative outcomes, complications, and risk factors with regard to visual prognosis were analyzed. Visual acuity was converted from the Snellen equivalent to logMAR values. RESULTS: This study included 51 men and 70 women with a mean ± SD age of 44.6 ± 18.4 years. The three most common diseases were idiopathic uveitis, Behcet's disease, and Vogt-Koyanagi-Harada disease. The best-corrected visual acuity improved from 1.52 ± 0.83 logMAR units preoperatively to 0.37 ± 0.59 logMAR units postoperative (p < 0.001). The most frequent postoperative complications were posterior capsular opacity (24 eyes) and cystoid macular edema (10 eyes). Anterior uveitis related to HLA-B27 had the best visual prognosis, whereas Behcet's disease had the poorest visual outcome (p = 0.029). Logistic regression analysis indicated that disease etiology (p = 0.011) and preoperative visual acuity (p = 0.020) were related to the postoperative visual prognosis. CONCLUSION: Cataract extraction can improve visual function for most patients with uveitis. Postoperative complications were not uncommon and Behcet's disease had the poorest postoperative visual prognosis.