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hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions.

Brocchieri L, Conway de Macario E, Macario AJ - BMC Evol. Biol. (2008)

Bottom Line: Nowadays, the study of chaperone genes benefits from the availability of genome sequences and a new protocol, chaperonomics, which we applied to elucidate the human hsp70 family.The human hsp70-gene family is characterized by a remarkable evolutionary diversity that mainly resulted from multiple duplications and retrotranspositions of a highly expressed gene, HSPA8.These functions may also be further defined by the observed differences in the N-terminal domain.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Florida, Department of Molecular Genetics and Microbiology and UF Genetics Institute, Gainesville, FL 32610, USA. lucianob@ufl.edu

ABSTRACT

Background: Hsp70 chaperones are required for key cellular processes and response to environmental changes and survival but they have not been fully characterized yet. The human hsp70-gene family has an unknown number of members (eleven counted over ten years ago); some have been described but the information is incomplete and inconsistent. A coherent body of knowledge encompassing all family components that would facilitate their study individually and as a group is lacking. Nowadays, the study of chaperone genes benefits from the availability of genome sequences and a new protocol, chaperonomics, which we applied to elucidate the human hsp70 family.

Results: We identified 47 hsp70 sequences, 17 genes and 30 pseudogenes. The genes distributed into seven evolutionarily distinct groups with distinguishable subgroups according to phylogenetic and other data, such as exon-intron and protein features. The N-terminal ATP-binding domain (ABD) was conserved at least partially in the majority of the proteins but the C-terminal substrate-binding domain (SBD) was not. Nine proteins were typical Hsp70s (65-80 kDa) with ABD and SBD, two were lighter lacking partly or totally the SBD, and six were heavier (>80 kDa) with divergent C-terminal domains. We also analyzed exon-intron features, transcriptional variants and protein structure and isoforms, and modality and patterns of expression in various tissues and developmental stages. Evolutionary analyses, including human hsp70 genes and pseudogenes, and other eukaryotic hsp70 genes, showed that six human genes encoding cytosolic Hsp70s and 27 pseudogenes originated from retro-transposition of HSPA8, a gene highly expressed in most tissues and developmental stages.

Conclusion: The human hsp70-gene family is characterized by a remarkable evolutionary diversity that mainly resulted from multiple duplications and retrotranspositions of a highly expressed gene, HSPA8. Human Hsp70 proteins are clustered into seven evolutionary Groups, with divergent C-terminal domains likely defining their distinctive functions. These functions may also be further defined by the observed differences in the N-terminal domain.

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Phylogenetic tree of atypical eukaryotic hsp70 genes. Included are the proteins encoded in the atypical human hsp70 genes (Groups III, IV, and V in Figure 1) and in the hsp70 genes of eighteen other completely sequenced eukaryotic genomes. Sequences from the latter eighteen non-human genomes were identified using as queries human proteins from Groups II, VI, and VII and the SSPA procedure [36]. The tree is rooted by the DnaK sequence (AAC73125.1) from E. coli (DnaK E. coli) and by representatives of typical human Hsp70s (from Groups II, VI, and VII). See legend to Figure 1 and text for details on methods and calculation of bootstrap values. Human proteins are in red. Acronyms in black indicate the eukaryotic genomes in which other hsp70 genes were found, as follows: ANOGA: Anopheles gambiae (Insects); ARATH: Arabidopsis thaliana (Plants); CANGL: Candida glabrata (Fungi); CAEEL: Caenorhabditis elegans (Nematoda); CHICK: Gallus gallus (Birds); CYAME: Cyanidioschyzon merolae (Red alga); DANRE: Danio rerio (Fish); DROME: Drosophila melanogaster (Insects); ENTHI: Entamoeba histolytica (Protists); LEIMA: Leishmania major (Protists); MOUSE: Mus musculus (Mammals); NEUCR: Neurospora crassa (Fungi); SCHPO: Schizosaccharomyces pombe (Fungi); TRYCR: Trypanosoma cruzi (Protists); XENTR: Xenopus tropicalis (Amphibians); YEAST: Saccharomyces caerevisiae (Fungi).
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Figure 3: Phylogenetic tree of atypical eukaryotic hsp70 genes. Included are the proteins encoded in the atypical human hsp70 genes (Groups III, IV, and V in Figure 1) and in the hsp70 genes of eighteen other completely sequenced eukaryotic genomes. Sequences from the latter eighteen non-human genomes were identified using as queries human proteins from Groups II, VI, and VII and the SSPA procedure [36]. The tree is rooted by the DnaK sequence (AAC73125.1) from E. coli (DnaK E. coli) and by representatives of typical human Hsp70s (from Groups II, VI, and VII). See legend to Figure 1 and text for details on methods and calculation of bootstrap values. Human proteins are in red. Acronyms in black indicate the eukaryotic genomes in which other hsp70 genes were found, as follows: ANOGA: Anopheles gambiae (Insects); ARATH: Arabidopsis thaliana (Plants); CANGL: Candida glabrata (Fungi); CAEEL: Caenorhabditis elegans (Nematoda); CHICK: Gallus gallus (Birds); CYAME: Cyanidioschyzon merolae (Red alga); DANRE: Danio rerio (Fish); DROME: Drosophila melanogaster (Insects); ENTHI: Entamoeba histolytica (Protists); LEIMA: Leishmania major (Protists); MOUSE: Mus musculus (Mammals); NEUCR: Neurospora crassa (Fungi); SCHPO: Schizosaccharomyces pombe (Fungi); TRYCR: Trypanosoma cruzi (Protists); XENTR: Xenopus tropicalis (Amphibians); YEAST: Saccharomyces caerevisiae (Fungi).

Mentions: Figure 3 displays an evolutionary tree of eukaryotic atypical Hsp70 proteins from completely sequenced genomes, including representatives of Protists, Plants, Fungi, and Animals encompassing Nematodes, Insects, Fish, Amphibians, and Mammals. In these genomes, we found sequences most closely related to human Group III, Group IV, and Group V. The tree is rooted by a group encompassing DnaK from E. coli and human mitochondrial HSPA9B and include, for comparison, other representatives of the human typical Hsp70s such as the ER-residing HSPA5 and the cytosolic HSPA8 proteins. As mentioned earlier, we excluded from the tree sequences of Group I (i.e., HSPA12A and B), which were too diverged from the other sequences to be used in the alignment. The tree in Figure 3 shows, similarly to those in preceding figures, that the relation between Groups III, IV, and V are uncertain, a likely consequence of their ancient divergence. Also noteworthy is that contrary to the trees in the previous figures, in the tree shown in Figure 3 Groups IV and V (represented in humans by HSPA14 and STCH, respectively) appear to have diverged from a common ancestor, with weak bootstrap support (32.5%) but consistent nonetheless with their similarity in molecular weight (about 60 kDa) and sequence domain composition (see later). Interestingly, the cluster including STCH (Group V) contained sequences from animals such as C. elegans (but not Drosophila) and from Protists (Enthamoeba) but not from Plants or Fungi, whereas the cluster containing HSPA14 (Group IV) included only sequences from Vertebrates. Apart from a single sequence (SCHPO4) from S. pombe of uncertain classification, the sequences of the high molecular weight proteins, corresponding to the human Group III, were distinguished into the two subgroups of 105/110 kDa and 170 kDa as in the human tree shown in Figure 1, with high bootstrap support (91.7% and 97.7%, respectively). Sequences of the 105/110 kDa subcluster (including the human HSPH1, HSPA4L and HSPA4) were present in various Protists and in higher eukaryotes, suggesting that they originated from an ancient gene duplication event. A duplication of the gene into two branches, corresponding respectively to the human sequences HSPA4 and HSPH1 (representing two of the three subgroups of Group III; Figure 1) appears to have occurred early in the evolution of the Vertebrate lineage, before the appearance of Tetrapods (amphibians, reptiles, birds, and mammals). A subsequent duplication of HSPA4 into two separate genes (corresponding to HSPA4 and HSPA4L) seems also to have occurred before the appearance of Tetrapods (as indicated by the position in the tree of the sequence DANRE20). Interestingly, no representatives of HSPA4L from fish or amphibian were found. Multiple paralogs from the HSPH1 and HSPA4 gene-lines seem to have been recently generated in the chicken genome. Unexpectedly, the cluster containing the 170 kDa subgroup of the human Group III (HYOU1) included only sequences from animals and plants, suggesting gene loss or divergence in other lineages, including Fungi.


hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions.

Brocchieri L, Conway de Macario E, Macario AJ - BMC Evol. Biol. (2008)

Phylogenetic tree of atypical eukaryotic hsp70 genes. Included are the proteins encoded in the atypical human hsp70 genes (Groups III, IV, and V in Figure 1) and in the hsp70 genes of eighteen other completely sequenced eukaryotic genomes. Sequences from the latter eighteen non-human genomes were identified using as queries human proteins from Groups II, VI, and VII and the SSPA procedure [36]. The tree is rooted by the DnaK sequence (AAC73125.1) from E. coli (DnaK E. coli) and by representatives of typical human Hsp70s (from Groups II, VI, and VII). See legend to Figure 1 and text for details on methods and calculation of bootstrap values. Human proteins are in red. Acronyms in black indicate the eukaryotic genomes in which other hsp70 genes were found, as follows: ANOGA: Anopheles gambiae (Insects); ARATH: Arabidopsis thaliana (Plants); CANGL: Candida glabrata (Fungi); CAEEL: Caenorhabditis elegans (Nematoda); CHICK: Gallus gallus (Birds); CYAME: Cyanidioschyzon merolae (Red alga); DANRE: Danio rerio (Fish); DROME: Drosophila melanogaster (Insects); ENTHI: Entamoeba histolytica (Protists); LEIMA: Leishmania major (Protists); MOUSE: Mus musculus (Mammals); NEUCR: Neurospora crassa (Fungi); SCHPO: Schizosaccharomyces pombe (Fungi); TRYCR: Trypanosoma cruzi (Protists); XENTR: Xenopus tropicalis (Amphibians); YEAST: Saccharomyces caerevisiae (Fungi).
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Figure 3: Phylogenetic tree of atypical eukaryotic hsp70 genes. Included are the proteins encoded in the atypical human hsp70 genes (Groups III, IV, and V in Figure 1) and in the hsp70 genes of eighteen other completely sequenced eukaryotic genomes. Sequences from the latter eighteen non-human genomes were identified using as queries human proteins from Groups II, VI, and VII and the SSPA procedure [36]. The tree is rooted by the DnaK sequence (AAC73125.1) from E. coli (DnaK E. coli) and by representatives of typical human Hsp70s (from Groups II, VI, and VII). See legend to Figure 1 and text for details on methods and calculation of bootstrap values. Human proteins are in red. Acronyms in black indicate the eukaryotic genomes in which other hsp70 genes were found, as follows: ANOGA: Anopheles gambiae (Insects); ARATH: Arabidopsis thaliana (Plants); CANGL: Candida glabrata (Fungi); CAEEL: Caenorhabditis elegans (Nematoda); CHICK: Gallus gallus (Birds); CYAME: Cyanidioschyzon merolae (Red alga); DANRE: Danio rerio (Fish); DROME: Drosophila melanogaster (Insects); ENTHI: Entamoeba histolytica (Protists); LEIMA: Leishmania major (Protists); MOUSE: Mus musculus (Mammals); NEUCR: Neurospora crassa (Fungi); SCHPO: Schizosaccharomyces pombe (Fungi); TRYCR: Trypanosoma cruzi (Protists); XENTR: Xenopus tropicalis (Amphibians); YEAST: Saccharomyces caerevisiae (Fungi).
Mentions: Figure 3 displays an evolutionary tree of eukaryotic atypical Hsp70 proteins from completely sequenced genomes, including representatives of Protists, Plants, Fungi, and Animals encompassing Nematodes, Insects, Fish, Amphibians, and Mammals. In these genomes, we found sequences most closely related to human Group III, Group IV, and Group V. The tree is rooted by a group encompassing DnaK from E. coli and human mitochondrial HSPA9B and include, for comparison, other representatives of the human typical Hsp70s such as the ER-residing HSPA5 and the cytosolic HSPA8 proteins. As mentioned earlier, we excluded from the tree sequences of Group I (i.e., HSPA12A and B), which were too diverged from the other sequences to be used in the alignment. The tree in Figure 3 shows, similarly to those in preceding figures, that the relation between Groups III, IV, and V are uncertain, a likely consequence of their ancient divergence. Also noteworthy is that contrary to the trees in the previous figures, in the tree shown in Figure 3 Groups IV and V (represented in humans by HSPA14 and STCH, respectively) appear to have diverged from a common ancestor, with weak bootstrap support (32.5%) but consistent nonetheless with their similarity in molecular weight (about 60 kDa) and sequence domain composition (see later). Interestingly, the cluster including STCH (Group V) contained sequences from animals such as C. elegans (but not Drosophila) and from Protists (Enthamoeba) but not from Plants or Fungi, whereas the cluster containing HSPA14 (Group IV) included only sequences from Vertebrates. Apart from a single sequence (SCHPO4) from S. pombe of uncertain classification, the sequences of the high molecular weight proteins, corresponding to the human Group III, were distinguished into the two subgroups of 105/110 kDa and 170 kDa as in the human tree shown in Figure 1, with high bootstrap support (91.7% and 97.7%, respectively). Sequences of the 105/110 kDa subcluster (including the human HSPH1, HSPA4L and HSPA4) were present in various Protists and in higher eukaryotes, suggesting that they originated from an ancient gene duplication event. A duplication of the gene into two branches, corresponding respectively to the human sequences HSPA4 and HSPH1 (representing two of the three subgroups of Group III; Figure 1) appears to have occurred early in the evolution of the Vertebrate lineage, before the appearance of Tetrapods (amphibians, reptiles, birds, and mammals). A subsequent duplication of HSPA4 into two separate genes (corresponding to HSPA4 and HSPA4L) seems also to have occurred before the appearance of Tetrapods (as indicated by the position in the tree of the sequence DANRE20). Interestingly, no representatives of HSPA4L from fish or amphibian were found. Multiple paralogs from the HSPH1 and HSPA4 gene-lines seem to have been recently generated in the chicken genome. Unexpectedly, the cluster containing the 170 kDa subgroup of the human Group III (HYOU1) included only sequences from animals and plants, suggesting gene loss or divergence in other lineages, including Fungi.

Bottom Line: Nowadays, the study of chaperone genes benefits from the availability of genome sequences and a new protocol, chaperonomics, which we applied to elucidate the human hsp70 family.The human hsp70-gene family is characterized by a remarkable evolutionary diversity that mainly resulted from multiple duplications and retrotranspositions of a highly expressed gene, HSPA8.These functions may also be further defined by the observed differences in the N-terminal domain.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Florida, Department of Molecular Genetics and Microbiology and UF Genetics Institute, Gainesville, FL 32610, USA. lucianob@ufl.edu

ABSTRACT

Background: Hsp70 chaperones are required for key cellular processes and response to environmental changes and survival but they have not been fully characterized yet. The human hsp70-gene family has an unknown number of members (eleven counted over ten years ago); some have been described but the information is incomplete and inconsistent. A coherent body of knowledge encompassing all family components that would facilitate their study individually and as a group is lacking. Nowadays, the study of chaperone genes benefits from the availability of genome sequences and a new protocol, chaperonomics, which we applied to elucidate the human hsp70 family.

Results: We identified 47 hsp70 sequences, 17 genes and 30 pseudogenes. The genes distributed into seven evolutionarily distinct groups with distinguishable subgroups according to phylogenetic and other data, such as exon-intron and protein features. The N-terminal ATP-binding domain (ABD) was conserved at least partially in the majority of the proteins but the C-terminal substrate-binding domain (SBD) was not. Nine proteins were typical Hsp70s (65-80 kDa) with ABD and SBD, two were lighter lacking partly or totally the SBD, and six were heavier (>80 kDa) with divergent C-terminal domains. We also analyzed exon-intron features, transcriptional variants and protein structure and isoforms, and modality and patterns of expression in various tissues and developmental stages. Evolutionary analyses, including human hsp70 genes and pseudogenes, and other eukaryotic hsp70 genes, showed that six human genes encoding cytosolic Hsp70s and 27 pseudogenes originated from retro-transposition of HSPA8, a gene highly expressed in most tissues and developmental stages.

Conclusion: The human hsp70-gene family is characterized by a remarkable evolutionary diversity that mainly resulted from multiple duplications and retrotranspositions of a highly expressed gene, HSPA8. Human Hsp70 proteins are clustered into seven evolutionary Groups, with divergent C-terminal domains likely defining their distinctive functions. These functions may also be further defined by the observed differences in the N-terminal domain.

Show MeSH