Construction of macromolecular assemblages in eukaryotic processes and their role in human disease: linking RINGs together.
Members of the Really Interesting New Gene (RING) family of proteins are found throughout the cells of eukaryotes and function in processes as diverse as development, oncogenesis, viral replication and apoptosis. There are over 200 members of the RING family where membership is based on the presence of a consensus sequence of zinc binding residues. Outside of these residues there is little sequence homology; however, there are conserved structural features. Current evidence strongly suggests that RINGs are protein interaction domains. We examine the features of RING binding motifs in terms of individual cases and the potential for finding a universal consensus sequence for RING binding domains (FRODOs). This review examines known and potential functions of RINGs, and attempts to develop a framework within which their seemingly multivalent cellular roles can be consistently understood in their structural and biochemical context. Interestingly, some RINGs can self-associate as well as bind other RINGs. The ability to self-associate is typically translated into the annoying propensity of these domains to aggregate during biochemical characterization. The RINGs of PML, BRCA1, RAG1, KAP1/TIF1beta, Polycomb proteins, TRAFs and the viral protein Z have been well characterized in terms of both biochemical studies and functional data and so will serve as focal points for discussion. We suggest physiological functions for the oligomeric properties of these domains, such as their role in formation of macromolecular assemblages which function in an intricate interplay of coupled metal binding, folding and aggregation, and participate in diverse functions: epigenetic regulation of gene expression, RNA transport, cell cycle control, ubiquitination, signal transduction and organelle assembly.
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D016384:Consensus Sequence; D005057:Eukaryotic Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007239:Infections / Q000378:metabolism; D046911:Macromolecular Substances; D008667:Metalloproteins / Q000737:chemistry / Q000145:classification / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000502:physiology; D009369:Neoplasms / Q000378:metabolism; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D015032:Zinc / Q000737:chemistry
D046911:Macromolecular Substances; D008667:Metalloproteins; D009363:Neoplasm Proteins; D015032:Zinc