Influence of oligomerization on the dynamics of G‐protein coupled receptors as assessed by normal mode analysis

Abstract

The recently discovered impact of oligomerization on G-protein coupled receptor (GPCR) function further complicates the already challenging goal of unraveling the molecular and dynamic mechanisms of these receptors. To help understand the effect of oligomerization on the dynamics of GPCRs, we have compared the motion of monomeric, dimeric, and tetrameric arrangements of the prototypic GPCR rhodopsin, using an approximate-yet powerful-normal mode analysis (NMA) technique termed elastic network model (ENM). Moreover, we have used ENM to discriminate between putative dynamic mechanisms likely to account for the recently observed conformational rearrangement of the TM4,5-TM4,5 dimerization interface of GPCRs that occurs upon activation. Our results indicate: (1) significant perturbation of the normal modes (NMs) of the rhodopsin monomer upon oligomerization, which is mainly manifested at interfacial regions; (2) increased positive correlation among the transmem-brane domains (TMs) and between the extracellular loop (EL) and TM regions of the rhodopsin protomer; (3) highest inter-residue positive correlation at the interfaces between protomers; and (4) experimentally testable hypotheses of differential motional changes within different putative oligomeric arrangements.

Computational and Experimental Analysis of the Transmembrane Domain 4/5 Dimerization Interface of the Serotonin 5-HT1A Receptor

“…In this arrangement, TM4, TM5, and IL2 (connecting TM3 and TM4) are involved in intradimeric interactions, whereas TM1, TM2, and IL3 (connecting TM5 and TM6) are involved in interdimeric interactions. We hypothesized that the dimeric organization in 5-HT 1A receptors is similar to that proposed for the rhodopsin Niv and Filizola, 2008) and dopamine receptors (Guo et al, 2005).…”

Normal mode analysis as a method to derive protein dynamics information from the Protein Data Bank

“…NMA has been applied to oligomeric proteins such as hemoglobin (Seno and Gō 1990a, b), G-protein coupled receptors (Niv and Filizola 2008), membrane proteins (Bahar et al 2010), and immunoglobulins (Wako and Endo 2012). It has also been applied to multimeric structures such as subtilisineglin c complexes (Ishida et al 1998), protein-DNA complexes (Yang et al 2006), and protein-RNA complexes (Wako and Endo 2013) to reveal the structure-function relationships, with particular attention to the influence of oligomerization and complex formation with other molecules.…”

Comparing the intrinsic dynamics of multiple protein structures using elastic network models

“…Similarly, Polles et al explored the flexibility in different assemblies of a heterogeneous set of virus capsids based on fluctuations-based analyses and domain decomposition [93]. Other studies dedicated to the comparison of dynamics to changes in oligomeric state have been reported for monomeric, dimeric and tetrameric states of GPCRs [94], dimeric and hexameric (trimer-of-dimer) states of the serine receptor Tsr [95], and monomeric and dimeric states of the p53 protein [96].…”