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A six-amino-acid motif is a major determinant in functional evolution of HOX1 proteins.

ABSTRACT: Gene duplication and divergence is a major driver in the emergence of evolutionary novelties. How variations in amino acid sequences lead to loss of ancestral activity and functional diversification of proteins is poorly understood. We used cross-species functional analysis of Drosophila Labial and its mouse HOX1 orthologs (HOXA1, HOXB1, and HOXD1) as a paradigm to address this issue. Mouse HOX1 proteins display low (30%) sequence similarity with Drosophila Labial. However, substituting endogenous Labial with the mouse proteins revealed that HOXA1 has retained essential ancestral functions of Labial, while HOXB1 and HOXD1 have diverged. Genome-wide analysis demonstrated similar DNA-binding patterns of HOXA1 and Labial in mouse cells, while HOXB1 binds to distinct targets. Compared with HOXB1, HOXA1 shows an enrichment in co-occupancy with PBX proteins on target sites and exists in the same complex with PBX on chromatin. Functional analysis of HOXA1-HOXB1 chimeric proteins uncovered a novel six-amino-acid C-terminal motif (CTM) flanking the homeodomain that serves as a major determinant of ancestral activity. In vitro DNA-binding experiments and structural prediction show that CTM provides an important domain for interaction of HOXA1 proteins with PBX. Our findings show that small changes outside of highly conserved DNA-binding regions can lead to profound changes in protein function.

SUBMITTER: Singh NP

PROVIDER: S-EPMC7706710 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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A six-amino-acid motif is a major determinant in functional evolution of HOX1 proteins.

Singh Narendra Pratap NP De Kumar Bony B Paulson Ariel A Parrish Mark E ME Zhang Ying Y Florens Laurence L Conaway Joan W JW Si Kausik K Krumlauf Robb R

Genes & development 20201112 23-24

Gene duplication and divergence is a major driver in the emergence of evolutionary novelties. How variations in amino acid sequences lead to loss of ancestral activity and functional diversification of proteins is poorly understood. We used cross-species functional analysis of <i>Drosophila</i> Labial and its mouse HOX1 orthologs (HOXA1, HOXB1, and HOXD1) as a paradigm to address this issue. Mouse HOX1 proteins display low (30%) sequence similarity with <i>Drosophila</i> Labial. However, substit ...[more]

PMID: 33184220

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Project description:BackgroundThe evolution of the full repertoire of proteins encoded in a given genome is mostly driven by gene duplications, deletions, and sequence modifications of existing proteins. Indirect information about relative rates and other intrinsic parameters of these three basic processes is contained in the proteome-wide distribution of sequence identities of pairs of paralogous proteins.ResultsWe introduce a simple mathematical framework based on a stochastic birth-and-death model that allows one to extract some of this information and apply it to the set of all pairs of paralogous proteins in H. pylori, E. coli, S. cerevisiae, C. elegans, D. melanogaster, and H. sapiens. It was found that the histogram of sequence identities p generated by an all-to-all alignment of all protein sequences encoded in a genome is well fitted with a power-law form approximately p-gamma with the value of the exponent gamma around 4 for the majority of organisms used in this study. This implies that the intra-protein variability of substitution rates is best described by the Gamma-distribution with the exponent alpha approximately 0.33. Different features of the shape of such histograms allow us to quantify the ratio between the genome-wide average deletion/duplication rates and the amino-acid substitution rate.ConclusionWe separately measure the short-term ("raw") duplication and deletion rates , which include gene copies that will be removed soon after the duplication event and their dramatically reduced long-term counterparts r(*)dup, r(*)del. High deletion rate among recently duplicated proteins is consistent with a scenario in which they didn't have enough time to significantly change their functional roles and thus are to a large degree disposable. Systematic trends of each of the four duplication/deletion rates with the total number of genes in the genome were analyzed. All but the deletion rate of recent duplicates r(*)del were shown to systematically increase with Ngenes. Abnormally flat shapes of sequence identity histograms observed for yeast and human are consistent with lineages leading to these organisms undergoing one or more whole-genome duplications. This interpretation is corroborated by our analysis of the genome of Paramecium tetraurelia where the p-4 profile of the histogram is gradually restored by the successive removal of paralogs generated in its four known whole-genome duplication events.

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A six-amino-acid motif is a major determinant in functional evolution of HOX1 proteins.

Publications

A six-amino-acid motif is a major determinant in functional evolution of HOX1 proteins.

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