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Evolution of the Vertebrate Paralemmin Gene Family: Ancient Origin of Gene Duplicates Suggests Distinct Functions
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Molecular Cell Biology.
2012 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 7, e41850- p.Article in journal (Refereed) Published
Abstract [en]

Paralemmin-1 is a protein implicated in plasma membrane dynamics, the development of filopodia, neurites and dendritic spines, as well as the invasiveness and metastatic potential of cancer cells. However, little is known about its mode of action, or about the biological functions of the other paralemmin isoforms: paralemmin-2, paralemmin-3 and palmdelphin. We describe here evolutionary analyses of the paralemmin gene family in a broad range of vertebrate species. Our results suggest that the four paralemmin isoform genes (PALM1, PALM2, PALM3 and PALMD) arose by quadruplication of an ancestral gene in the two early vertebrate genome duplications. Paralemmin-1 and palmdelphin were further duplicated in the teleost fish specific genome duplication. We identified a unique sequence motif common to all paralemmins, consisting of 11 highly conserved residues of which four are invariant. A single full-length paralemmin homolog with this motif was identified in the genome of the sea lamprey Petromyzon marinus and an isolated putative paralemmin motif could be detected in the genome of the lancelet Branchiostoma floridae. This allows us to conclude that the paralemmin gene family arose early and has been maintained throughout vertebrate evolution, suggesting functional diversification and specific biological roles of the paralemmin isoforms. The paralemmin genes have also maintained specific features of gene organisation and sequence. This includes the occurrence of closely linked downstream genes, initially identified as a readthrough fusion protein with mammalian paralemmin-2 (Palm2-AKAP2). We have found evidence for such an arrangement for paralemmin-1 and -2 in several vertebrate genomes, as well as for palmdelphin and paralemmin-3 in teleost fish genomes, and suggest the name paralemmin downstream genes (PDG) for this new gene family. Thus, our findings point to ancient roles for paralemmins and distinct biological functions of the gene duplicates.

Place, publisher, year, edition, pages
2012. Vol. 7, no 7, e41850- p.
Keyword [en]
genome duplication, molecular characterization, chromosome duplications, membrane dynamics, amphioxus genome, teleost fishes, protein family, insights, reveals, identification
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-184483DOI: 10.1371/journal.pone.0041850ISI: 000306806600134OAI: diva2:565727
Available from: 2012-11-08 Created: 2012-11-07 Last updated: 2013-12-03Bibliographically approved
In thesis
1. Protein Folding, Binding and Evolution: PDZ domains and paralemmins as model systems
Open this publication in new window or tab >>Protein Folding, Binding and Evolution: PDZ domains and paralemmins as model systems
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins present at the synapse need to be multitasking in order to perform all vital functions in this limited space. In this thesis I have analyzed the function and evolution of such proteins, focusing on the PDZ domain and the paralemmin family. The PDZ domains bind to a wide variety of interaction partners. The affinity for each partner is regulated by residues at the binding site, but also through intradomain allostery. How this intradomain allostery is transferred to the binding site is not established. I here show that side chain interactions can explain all transfer of intradomain allostery in three analyzed PDZ domains. A circularly permuted PDZ domain has an identical set of amino acids as the original protein and a very similar structure with only a few perturbed side chains. By using the circular permutant I show that a slight alteration in the position of a side chain leads to a corresponding change in allosteric signal. I further study the folding of several PDZ domains and show that they all fold via a conserved folding mechanism, supporting the notion that the final structure has a part in deciding folding mechanism. The folding mechanism of the circularly permuted PDZ domain is conserved compared to the original protein illustrating how circular permutations can be tolerated through evolution. The multifunctionality of paralemmins probably lies in their highly flexible structures. I have studied the evolution of the paralemmins and found that the four mammalian paralemmins arose in the two whole-genome duplications that occurred early in the vertebrate evolution. The fact that all four paralemmins have survived evolution since the gene duplications suggests that they have important functions, possibly in the development of the nervous system. Synaptic proteins are crucial for many biological processes, and their misfolding implicated in many diseases. The results presented here shed light on the mechanisms of action of the synaptic proteins and will help us to understand how they generate disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 47 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1006
Protein folding, evolution, binding, allostery, Paralemmin, PDZ domain
National Category
Biochemistry and Molecular Biology Structural Biology Genetics
urn:nbn:se:uu:diva-185573 (URN)978-91-554-8563-4 (ISBN)
Public defence
2013-02-01, B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Available from: 2013-01-11 Created: 2012-11-26 Last updated: 2013-02-11Bibliographically approved

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