RESUMEN
Phosphotyrosine-binding domains, typified by the SH2 (Src homology 2) and PTB domains, are critical upstream components of signal transduction pathways. The E3 ubiquitin ligase Hakai targets tyrosine-phosphorylated E-cadherin via an uncharacterized domain. In this study, the crystal structure of Hakai (amino acids 106-206) revealed that it forms an atypical, zinc-coordinated homodimer by utilizing residues from the phosphotyrosine-binding domain of two Hakai monomers. Hakai dimerization allows the formation of a phosphotyrosine-binding pocket that recognizes specific phosphorylated tyrosines and flanking acidic amino acids of Src substrates, such as E-cadherin, cortactin and DOK1. NMR and mutational analysis identified the Hakai residues required for target binding within the binding pocket, now named the HYB domain. ZNF645 also possesses a HYB domain but demonstrates different target specificities. The HYB domain is structurally different from other phosphotyrosine-binding domains and is a potential drug target due to its novel structural features.
Asunto(s)
Cadherinas/metabolismo , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/metabolismo , Secuencia de Aminoácidos , Cristalografía por Rayos X , Análisis Mutacional de ADN , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Estructura Terciaria de ProteínaRESUMEN
Lymphogranuloma venereum (LGV) typing was performed on chlamydia-positive samples obtained in Sydney, Australia, between 2005 and 2007, from community-based cohorts of predominantly asymptomatic HIV-infected and -uninfected men who have sex with men. The number of chlamydia tests and follow-up for each cohort were as follows: 2082 (90.2% of eligible visits) over 2005.1 person-years (PY) of follow-up in the HIV-uninfected cohort; and 521 (70.8% of eligible visits) over 320.2 PY of follow-up in the HIV-infected cohort. One case of rectal LGV in a symptomatic HIV-infected participant was identified among 64 Chlamydia trachomatis infections, giving an LGV incidence in the HIV-infected cohort of 0.3 per 100 PY, 95% Confidence Interval 0.008-1.7. Routine LGV typing of chlamydia infections in asymptomatic Australian men who have sex with men does not appear justified.