The ferlin gene family are characterised by multiple tandem C2 domains and a C-terminal transmembrane domain. They are found in a wide range of species and their function remains unknown, however, mutations in its two most well-characterised members, dysferlin and otoferlin, have been implicated in human disease [ (PUBMED:20667140) ].
This is central domain A in proteins of the Ferlin family [ (PUBMED:15112237) ].
Ferlins: regulators of vesicle fusion for auditory neurotransmission, receptortrafficking and membrane repair.
Traffic. 2012; 13: 185-94
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Ferlins are a family of multiple C2 domain proteins with emerging roles invesicle fusion and membrane trafficking. Ferlin mutations are associated withmuscular dystrophy (dysferlin) and deafness (otoferlin) in humans, andinfertility in Caenorhabditis elegans (Fer-1) and Drosophila (misfire),demonstrating their importance for normal cellular functioning. Ferlins showancient origins in eukaryotic evolution and are detected in all eukaryotickingdoms, including unicellular eukaryotes and apicomplexian protists, suggestingorigins in a common ancestor predating eukaryotic evolutionary branching. Thecharacteristic feature of the ferlin family is their multiple tandem cytosolic C2domains (five to seven C2 domains), the most of any protein family, and anextremely rare feature amongst eukaryotic proteins. Ferlins also bear a uniquenested DysF domain and small conserved 60-70 residue ferlin-specific sequences(Fer domains). Ferlins segregate into two subtypes based on the presence (type I ferlin) or absence (type II ferlin) of the DysF and FerA domains. Ferlins havediverse tissue-specific and developmental expression patterns, with ferlin animalmodels united by pathologies arising from defects in vesicle fusion. Consistentwith their proposed role in vesicle trafficking, ferlin interaction partnersinclude cytoskeletal motors, other vesicle-associated trafficking proteins andtransmembrane receptors or channels. Herein we summarize the research history of the ferlins, an intriguing family of structurally conserved proteins with apreserved ancestral function as regulators of vesicle fusion and receptortrafficking.
Phylogenetic analysis of ferlin genes reveals ancient eukaryotic origins.
BMC Evol Biol. 2010; 10: 231-231
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BACKGROUND: The ferlin gene family possesses a rare and identifying featureconsisting of multiple tandem C2 domains and a C-terminal transmembrane domain.Much currently remains unknown about the fundamental function of this genefamily, however, mutations in its two most well-characterised members, dysferlin and otoferlin, have been implicated in human disease. The availability of genome sequences from a wide range of species makes it possible to explore the evolutionof the ferlin family, providing contextual insight into characteristic featuresthat define the ferlin gene family in its present form in humans. RESULTS: Ferlingenes were detected from all species of representative phyla, with two ferlinsubgroups partitioned within the ferlin phylogenetic tree based on the presenceor absence of a DysF domain. Invertebrates generally possessed two ferlin genes(one with DysF and one without), with six ferlin genes in most vertebrates (threeDysF, three non-DysF). Expansion of the ferlin gene family is evident between thedivergence of lamprey (jawless vertebrates) and shark (cartilaginous fish).Common to almost all ferlins is an N-terminal C2-FerI-C2 sandwich, a FerB motif, and two C-terminal C2 domains (C2E and C2F) adjacent to the transmembrane domain.Preservation of these structural elements throughout eukaryotic evolutionsuggests a fundamental role of these motifs for ferlin function. In contrast,DysF, C2DE, and FerA are optional, giving rise to subtle differences in domaintopologies of ferlin genes. Despite conservation of multiple C2 domains in allferlins, the C-terminal C2 domains (C2E and C2F) displayed higher sequenceconservation and greater conservation of putative calcium binding residues acrossparalogs and orthologs. Interestingly, the two most studied non-mammalian ferlins(Fer-1 and Misfire) in model organisms C. elegans and D. melanogaster, present asoutgroups in the phylogenetic analysis, with results suggestingreproduction-related divergence and specialization of species-specific functions within their genus. CONCLUSIONS: Our phylogenetic studies provide evolutionaryinsight into the ferlin gene family. We highlight the existence of ferlin-likeproteins throughout eukaryotic evolution, from unicellular phytoplankton andapicomplexan parasites, through to humans. We characterise the preservation offerlin structural motifs, not only of C2 domains, but also the more poorlycharacterised ferlin-specific motifs representing the DysF, FerA and FerBdomains. Our data suggest an ancient role of ferlin proteins, with lessons fromvertebrate biology and human disease suggesting a role relating to vesicle fusionand plasma membrane specialization.
Insights into the evolution of the nucleolus by an analysis of its protein domainrepertoire.
Bioessays. 2004; 26: 567-81
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Recently, the first investigation of nucleoli using mass spectrometry led to the identification of 271 proteins. This represents a rich resource for acomprehensive investigation of nucleolus evolution. We applied a protocol for theidentification of known and novel conserved protein domains of the nucleolus,resulting in the identification of 115 known and 91 novel domain profiles. Thephyletic distribution of nucleolar protein domains in a collection of completeproteomes of selected organisms from all domains of life confirms thearchaebacterial origin of the core machinery for ribosome maturation andassembly, but also reveals substantial eubacterial and eukaryotic contributionsto nucleolus evolution. We predict that, in different phases of nucleolusevolution, protein domains with different biochemical functions were recruited tothe nucleolus. We suggest a model for the late and continuous evolution of thenucleolus in early eukaryotes and argue against an endosymbiotic origin of thenucleolus and the nucleus. Supplementary material for this article can be foundon the BioEssays website athttp://www.interscience.wiley.com/jpages/0265-9247/suppmat/index.html.
Links (links to other resources describing this domain)
