ARPCOMPLEXITY
ERC funded synergy grant defining the role of Arp2/3 complex isoforms at multiple scales of biology
The Arp2/3 complex consisting of seven subunits (Arp2, Arp3 and ARPC1–5) is conserved from yeast to man and plays an essential role in generating branched actin filament networks that provide the driving force and structural support for the physical integrity of cells, and a wide range of fundamental cellular processes including membrane trafficking and cell migration.
Interestingly, in humans and other mammals, Arp3, ARPC1 and ARPC5 exist as two different isoforms (Arp3/Arp3B, ARPC1A/ARPC1B and ARPC5/ARPC5L) that are 91, 67 and 67% identical respectively. The presence of these subunit isoforms suggests that the mammalian Arp2/3 complex is actually a family of 8 iso-complexes with specific cellular or physiological functions.
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The Way lab previously demonstrated that ARPC1 and ARPC5 isoforms confer different actin nucleating properties to the Arp2/3 complex (Abella 2016, PMID:26655834). We have also established that Arp3 and Arp3B containing complexes have different cellular properties, with those with Arp3B enhancing branched actin network disassembly (Galloni 2021, PMID: 34106209). In addition, the Gomes lab has demonstrated that the ARPC5 isoforms play unique roles in T-tubule organization and nuclei positioning in skeletal muscle (Roman 2017, PMID:28892082).
The importance of Arp2/3 isoforms in tissue homeostasis is also underscored by the finding that loss of function mutations in human ARPC1B lead to Wiskott-Aldrich syndrome like symptoms including severe inflammation and immunodeficiency as well as impaired cytotoxic T lymphocyte maintenance and cytolytic activity (Kahr 2017 PMID:28368018 and Randzavola 2019, PMID:31710310).
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The task ahead is to investigate whether the eight different Arp2/3 complexes have unique activities, interactions, cellular or physiological functions. ARPComplexity is an ERC funded synergy grant involving the labs of Michael Way (Crick Institute London), Carolyn Moores (Birkbeck College, London) and Edgar Gomes (IMM, Lisbon, Portugal). We aim to understand the role of Arp2/3 complex diversity at three hierarchies of biology (molecular, cellular and physiological).
This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme.
Grant agreement No 810207
ARPCOMPLEXITY TEAM MEMBERS
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GOMES LAB
Ana Raquel Pereira - Postdoc
Ana Soares - Postdoc
Catarina Sequeira - PhD Student
Helena Pinheiro - Research Scientist
MOORES LAB
Alana Cowell - Postdoc
Tianyang Liu - Postdoc
Ramteen Shayan - Postdoc
WAY LAB
Shaina Huang - PhD Student
Olivia Hill - PhD Student
Yan Cao - Postdoc
Luiz Ricardo da Costa Vasconcellos - Postdoc
Naoko Kogata - Research Scientist
Miroslav Mladenov - Research Scientist
PAST TEAM MEMBERS
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GOMES LAB
Francisco Calero-Cuenca - Postdoc - now a professional training teacher at the Community of Madrid, Spain
Luis Oliveira - Research Scientist - now an analyst at Central European Bank, Frankfurt Germany.
Graciano Leal - Postdoc - now R & D Scientist at Inflammatix, Lisbon
MOORES LAB
Fiona Shilliday - Postdoc - now at AstraZeneca Cambridge UK
WAY LAB
Davide Carra - PhD student - now Postdoc with Leonardo Morsut, USC, Los Angeles, USA
ARPCOMPLEXITY PUBLICATIONS AND PREPRINTS
MICAL2 ENHANCES BRANCHED ACTIN NETWORK DISASSEMBLY BY OXIDIZING ARP3B-CONTAINING ARP2/3 COMPLEXES.
Chiara Galloni, Davide Carra, Jasmine V. G. Abella, Svend Kjær, Pavithra
Singaravelu, David J Barry, Naoko Kogata, Christophe Guérin, Laurent Blanchoin and Michael Way
J. Cell Biol. 220:e202102043. 2021
doi:10.1083/jcb.202102043 PMID: 34106209
CRYO-EM OF HUMAN ARP2/3 COMPLEXES PROVIDES STRUCTURAL INSIGHTS INTO ACTIN NUCLEATION MODULATION BY ARPC5 ISOFORMS
Ottilie von Loeffelholz, Andrew Purkiss, Luyan Cao, Svend Kjaer, Naoko Kogata, Guillaume Romet-Lemonne, Michael Way and Carolyn A. Moores
Biology Open 9, bio054304 (2020)
doi:10.1242/bio.054304 PMID: 32661131