Structure--function relationships in HIV-1 Nef

Abstract

The accessory Nef protein of HIV and SIV is essential for viral pathogenesis, yet it is perplexing in its multitude of molecular functions. In this review we analyse the structure-function relationships of motifs recently proposed to play roles in aspects of Nef modification, signalling and trafficking, and thereby to impinge on the ability of the virus to survive in, and to manipulate, its cellular host. Based on the full-length structure assembly of HIV Nef, we correlate surface accessibility with secondary structure elements and sequence conservation. Motifs involved in Nef-mediated CD4 and MHC I downregulation are located in flexible regions of Nef, suggesting that the formation of the transient trafficking complexes involved in these processes depends on the recognition of primary sequences. In contrast, the interaction sites for signalling molecules that contain SH3 domains or the p21-activated kinases are associated with the well folded core domain, suggesting the recognition of highly structured protein surfaces.

Fig. 1. Location of functional motifs in the HIV-1 Nef structure. (A) Functional motifs in HIV-1 Nef (Table II) and their location in the full-length structure as derived from the NMR structure assembly. Binding sites for the known interacting proteins are indicated. (B) The van der Waals surface presentation of Nef indicates the accessibility of the interacting residues. The colour coding corresponds to the labelled residues in (A).

Fig. 2. Sequence conservation superimposed onto the surface and the backbone structure of HIV-1 Nef. The colour coding corresponds to the degree of conservation ranging from 30% (orange) to 84% (white, average conservation) to 100% (blue). Some of the interaction sites listed in Table I are indicated on the structure. The figure was generated with GRASP (Nicholls et al., 1991).

Matthias Geyer, Oliver T. Fackler & B. Matija Peterlin