Abstract
BackgroundChaperonin proteins are well known for the critical role they play in protein folding and in disease. However, the recent identification of three diverged chaperonin paralogs associated with the human Bardet-Biedl and McKusick-Kaufman Syndromes (BBS and MKKS, respectively) indicates that the eukaryotic chaperonin-gene family is larger and more differentiated than previously thought. The availability of complete genome sequences makes possible a definitive characterization of the complete set of chaperonin sequences in human and other species.ResultsWe identified fifty-four chaperonin-like sequences in the human genome and similar numbers in the genomes of the model organisms mouse and rat. In mammal genomes we identified, besides the well-known CCT chaperonin genes and the three genes associated with the MKKS and BBS pathological conditions, a newly-defined class of chaperonin genes named CCT8L, represented in human by the two sequences CCT8L1 and CCT8L2. Comparative analyses from several vertebrate genomes established the monophyletic origin of chaperonin-like MKKS and BBS genes from the CCT8 lineage. The CCT8L gene originated from a later duplication also in the CCT8 lineage at the onset of mammal evolution and duplicated in primate genomes. The functionality of CCT8L genes in different species was confirmed by evolutionary analyses and in human by expression data. Detailed sequence analysis and structural predictions of MKKS, BBS and CCT8L proteins strongly suggested that they conserve a typical chaperonin-like core structure but that they are unlikely to form a CCT-like oligomeric complex. The characterization of many newly-discovered chaperonin pseudogenes uncovered the intense duplication activity of eukaryotic chaperonin genes.ConclusionsIn vertebrates, chaperonin genes, driven by intense duplication processes, have diversified into multiple classes and functionalities that extend beyond their well-known protein-folding role as part of the typical oligomeric chaperonin complex, emphasizing previous observations on the involvement of individual CCT monomers in microtubule elongation. The functional characterization of newly identified chaperonin genes will be a challenge for future experimental analyses.
Highlights
Chaperonin proteins are well known for the critical role they play in protein folding and in disease
Three sequences corresponded to the Bardet-Biedl Syndrome (BBS) genes MKKS, BBS10 and BBS12
We recovered two additional uncharacterized sequences designated in the NCBI Entrez Gene database as CCT8L1 and CCT8L2
Summary
Chaperonin proteins are well known for the critical role they play in protein folding and in disease. Hsp60-like chaperonin proteins are well known for their role in assisting protein folding and in protecting cells from the deleterious effects of stress [1,2,3,4,5]. The eukaryotic cell expresses representatives of two distinct groups of chaperonin genes that are otherwise typical of bacteria (Group I) or archaea (Group II). Chaperonin proteins form typical multi-subunit double-ringed structures collectively called “chaperonins” [9,10,11,12,13]. Eukaryotic Group II chaperonin proteins assemble in a similar double-ringed oligomeric structure, called TRiC or CCT complex [15], composed of 16 subunits that in human are encoded by nine distinct genes (tcp1/cct, cct, cct6A-B, cct7-8) [8,9,10]. The CCT complex is mostly known for its role in folding the cytoskeleton proteins actin and tubulin [7,16] and mutations in individual CCT subunits lead to defects in the functioning of the cytoskeleton and mitosis arrest [17]
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