Phylogenetic analysis of Harmonin homology domains

Abstract Background Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in terms of function, allowing for direct binding to a partner as well as regulating the affinity and specificity of a...

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Main Authors: Baptiste Colcombet-Cazenave, Karen Druart, Crystel Bonnet, Christine Petit, Olivier Spérandio, Julien Guglielmini, Nicolas Wolff
Format: Article
Language:English
Published: BMC 2021-04-01
Series:BMC Bioinformatics
Subjects:
Online Access:https://doi.org/10.1186/s12859-021-04116-5
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author Baptiste Colcombet-Cazenave
Karen Druart
Crystel Bonnet
Christine Petit
Olivier Spérandio
Julien Guglielmini
Nicolas Wolff
author_facet Baptiste Colcombet-Cazenave
Karen Druart
Crystel Bonnet
Christine Petit
Olivier Spérandio
Julien Guglielmini
Nicolas Wolff
author_sort Baptiste Colcombet-Cazenave
collection DOAJ
description Abstract Background Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in terms of function, allowing for direct binding to a partner as well as regulating the affinity and specificity of adjacent domains for their own targets. Adding their small size and rather simple fold, HHDs appear as convenient modules to regulate protein–protein interactions in various biological contexts. Surprisingly, only nine HHDs have been detected in six proteins, mainly expressed in sensory neurons. Results Here, we built a profile Hidden Markov Model to screen the entire UniProtKB for new HHD-containing proteins. Every hit was manually annotated, using a clustering approach, confirming that only a few proteins contain HHDs. We report the phylogenetic coverage of each protein and build a phylogenetic tree to trace the evolution of HHDs. We suggest that a HHD ancestor is shared with Paired Amphipathic Helices (PAH) domains, a four-helix bundle partially sharing fold and functional properties. We characterized amino-acid sequences of the various HHDs using pairwise BLASTP scoring coupled with community clustering and manually assessed sequence features among each individual family. These sequence features were analyzed using reported structures as well as homology models to highlight structural motifs underlying HHDs fold. We show that functional divergence is carried out by subtle differences in sequences that automatized approaches failed to detect. Conclusions We provide the first HHD databases, including sequences and conservation, phylogenic trees and a list of HHD variants found in the auditory system, which are available for the community. This case study highlights surprising phylogenetic properties found in orphan domains and will assist further studies of HHDs. We unveil the implication of HHDs in their various binding interfaces using conservation across families and a new protein–protein surface predictor. Finally, we discussed the functional consequences of three identified pathogenic HHD variants involved in Hoyeraal-Hreidarsson syndrome and of three newly reported pathogenic variants identified in patients suffering from Usher Syndrome.
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spelling doaj.art-12eee5153b73430baa1ef47a5ff11ebe2022-12-21T19:47:07ZengBMCBMC Bioinformatics1471-21052021-04-0122112010.1186/s12859-021-04116-5Phylogenetic analysis of Harmonin homology domainsBaptiste Colcombet-Cazenave0Karen Druart1Crystel Bonnet2Christine Petit3Olivier Spérandio4Julien Guglielmini5Nicolas Wolff6Unité Récepteurs-Canaux, Institut PasteurUnité de Bio-Informatique Structurale, Institut PasteurUnité de Génétique et Physiologie de l’Audition, Institut PasteurUnité de Génétique et Physiologie de l’Audition, Institut PasteurUnité de Bio-Informatique Structurale, Institut PasteurHub de Bioinformatique et Biostatistique – Département Biologie Computationnelle, USR 3756 CNRS, Institut PasteurUnité Récepteurs-Canaux, Institut PasteurAbstract Background Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in terms of function, allowing for direct binding to a partner as well as regulating the affinity and specificity of adjacent domains for their own targets. Adding their small size and rather simple fold, HHDs appear as convenient modules to regulate protein–protein interactions in various biological contexts. Surprisingly, only nine HHDs have been detected in six proteins, mainly expressed in sensory neurons. Results Here, we built a profile Hidden Markov Model to screen the entire UniProtKB for new HHD-containing proteins. Every hit was manually annotated, using a clustering approach, confirming that only a few proteins contain HHDs. We report the phylogenetic coverage of each protein and build a phylogenetic tree to trace the evolution of HHDs. We suggest that a HHD ancestor is shared with Paired Amphipathic Helices (PAH) domains, a four-helix bundle partially sharing fold and functional properties. We characterized amino-acid sequences of the various HHDs using pairwise BLASTP scoring coupled with community clustering and manually assessed sequence features among each individual family. These sequence features were analyzed using reported structures as well as homology models to highlight structural motifs underlying HHDs fold. We show that functional divergence is carried out by subtle differences in sequences that automatized approaches failed to detect. Conclusions We provide the first HHD databases, including sequences and conservation, phylogenic trees and a list of HHD variants found in the auditory system, which are available for the community. This case study highlights surprising phylogenetic properties found in orphan domains and will assist further studies of HHDs. We unveil the implication of HHDs in their various binding interfaces using conservation across families and a new protein–protein surface predictor. Finally, we discussed the functional consequences of three identified pathogenic HHD variants involved in Hoyeraal-Hreidarsson syndrome and of three newly reported pathogenic variants identified in patients suffering from Usher Syndrome.https://doi.org/10.1186/s12859-021-04116-5Harmonin homology domainsProfile HMMScreeningPhylogenyUsher syndromeSequence analysis
spellingShingle Baptiste Colcombet-Cazenave
Karen Druart
Crystel Bonnet
Christine Petit
Olivier Spérandio
Julien Guglielmini
Nicolas Wolff
Phylogenetic analysis of Harmonin homology domains
BMC Bioinformatics
Harmonin homology domains
Profile HMM
Screening
Phylogeny
Usher syndrome
Sequence analysis
title Phylogenetic analysis of Harmonin homology domains
title_full Phylogenetic analysis of Harmonin homology domains
title_fullStr Phylogenetic analysis of Harmonin homology domains
title_full_unstemmed Phylogenetic analysis of Harmonin homology domains
title_short Phylogenetic analysis of Harmonin homology domains
title_sort phylogenetic analysis of harmonin homology domains
topic Harmonin homology domains
Profile HMM
Screening
Phylogeny
Usher syndrome
Sequence analysis
url https://doi.org/10.1186/s12859-021-04116-5
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