Length analyses of mammalian G-protein-coupled receptors

G-protein-coupled receptors (GPCRs) play a crucial role in mediating effect s of extracellular messengers in a wide variety of biological systems, comp rising the largest gene superfamily at least in mammals. Mammalian GPCRs ar e broadly classified into three families based on pharmacological propertie s and sequence similarities. These sequence similarities are largely confin ed to the seven transmembrane domains, and much less in the extracellular a nd intracellular loops and terminals (LTs). Together with the fact that the LTs vary considerably in length and sequence, the LT length of GPCRs has n ot been studied systematically. Here we have applied a statistical analysis to the length of the LTs of a wide variety of mammalian GPCRs in order to examine the existence of any trends in molecular architecture among a known mammalian GPCR population. Tree diagrams constructed by cluster analyses, using eight length factors in a given GPCR, revealed possible length relati ons among GPCRs and defined at least three groups. Most samples in Group J (joined) and Group M (minor) had an exceptionally long N-terminal and I3 lo op, respectively; and other samples were considered as Group O (other/origi nal). This length-based classification largely coincided with the conventio nal sequence- and pharmacology-based classification, suggesting that the LT length contains some biological information when analysed at the populatio n level. Principle component analyses suggested the existence of inherent l ength differences between loops and terminals as well as between extracellu lar and intracellular LTs. Wilcoxon rank transformation tests unveiled stat istically significant differences between Group O and Group J, not only in the N-terminal and I3 loop, but also in the E3 loop. Correlation analyses i dentified an E1-I2 length-correlation in Group O and Group J and an N-E3 le ngth-correlation in Group J. Taken together, these results suggest a possib le functional importance of LT length in the GPCR superfamily. (C) 2001 Aca demic Press.