Professor Helen Walden

Professor of Structural Biology, Head of School (Molecular Biosciences) (Molecular Biosciences)

telephone: 01413307212
email: Helen.Walden@glasgow.ac.uk
pronouns: She/her/hers

Personal assistant: Miss Libby Hendrie
telephone: 1942
email: Libby.Hendrie@glasgow.ac.uk

Biography

Helen obtained her BSc in Biochemistry from the University of Bath in 1998. She then moved to the University of St Andrews for her PhD, investigating the structural basis of protein hyperthermostability. In 2001, she moved to Memphis, Tennessee for a postdoc in the newly-established lab of Brenda Schulman at St Jude's Children's Research Hospital. It was here that Helen developed her interest in the mechanisms of ubiquitination, solving the structure of the E1 for Nedd8. In 2005, Helen moved to the Lincoln's Inn Fields Laboratories of CRUK’s London Research Institute (now Francis Crick Institute), to establish her own group. After tenure, Helen moved to the MRC-Phosphorylation and Ubiquitylation Unit at the University of Dundee from 2013, and in 2017 relocated her lab to the University of Glasgow as Professor of Structural Biology. Helen was a member of the EMBO Young Investigator Programme from 2011 to 2014, and received the Colworth medal from the Biochemical Society in 2015, and in 2016 she received an ERC Consolidator award.

Research interests

How are specific ubiquitin signals produced? How is the right target selected, modified at the right site, at the right time, in the right pathway? The range of signals that can be produced is dizzying, with multiple mono signals, poly signals, and branched signals all part of the cell’s repertoire. However, the mechanistic basis for specificity is still unclear.

We use a range of techniques, including X-ray crystallography, and two model systems to tackle these questions: 1) an exquisitely specific E3 ligase that targets one site for modification, functions with limited auxiliary enzymes including E2s, and performs only one type of ubiquitination. 2) a broad-spectrum, promiscuous ligase that uses multiple E2s, to effect multiple signals. Both models are pertinent to human disease, with the specific E3 ligase, FANCL, mutated in patients with Fanconi Anemia, and the broad spectrum ligase, Parkin, mutated in early onset Parkinsonism.

In recent years, we have defined the molecular basis both of specific E2 selection, and how non-selective broad-spectrum E2 use is achieved. We have determined the mechanism of regulation of Parkin via autoinhibition, and established the molecular basis for activation. Our detailed understanding of the specificity in the Fanconi Anemia pathway has allowed us to begin developing small molecules to target the pathway. Our future aims are to define the structural basis for target selection, and specific signal transfer.

Research groups

Protein Structure & Regulation

Publications

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Number of items: 54.

2024

Rennie, M. L. , Gundogdu, M., Arkinson, C., Liness, S., Frame, S. and Walden, H. (2024) Structural and biochemical insights on the mechanism of action of the clinical USP1 inhibitor, KSQ-4279. Journal of Medicinal Chemistry, (doi: 10.1021/acs.jmedchem.4c01184) (PMID:39190802) (Early Online Publication)

Koszela, J., Rintala-Dempsey, A., Salzano, G. , Pimenta, V., Kamarainen, O., Gabrielsen, M. , Parui, A. L. , Shaw, G. S. and Walden, H. (2024) A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1. bioRxiv, (doi: 10.1101/2024.06.03.597144)

2023

Agirre, J. et al. (2023) The CCP 4 suite: integrative software for macromolecular crystallography. Acta Crystallographica. Section D: Structural Biology, D79(6), pp. 449-461. (doi: 10.1107/S2059798323003595)

Lemonidis, K. , Rennie, M. L. , Arkinson, C., Chaugule, V. K. , Clarke, M. , Streetley, J. and Walden, H. (2023) Structural and biochemical basis of interdependent FANCI-FANCD2 ubiquitination. EMBO Journal, 42(3), e111898. (doi: 10.15252/embj.2022111898) (PMID:36385258) (PMCID:PMC9890228)

2022

Rennie, M. L. , Arkinson, C., Chaugule, V. K. and Walden, H. (2022) Cryo-EM reveals a mechanism of USP1 inhibition through a cryptic binding site. Science Advances, 8(39), eabq6353. (doi: 10.1126/sciadv.abq6353) (PMID:36170365) (PMCID:PMC9519042)

Lemonidis, K. , Arkinson, C., Rennie, M. L. and Walden, H. (2022) Mechanism, specificity and function of FANCD2‐FANCI ubiquitination and deubiquitination. FEBS Journal, 289(16), pp. 4811-4829. (doi: 10.1111/febs.16077) (PMID:34137174)

Dunkerley, K. M., Rintala-Dempsey, A. C., Salzano, G. , Tadayon, R., Hadi, D., Barber, K. R., Walden, H. and Shaw, G. S. (2022) Distinct phosphorylation signals drive acceptor versus free ubiquitin chain targeting by Parkin. Biochemical Journal, 479(6), pp. 751-766. (doi: 10.1042/bcj20210741) (PMID:35262643) (PMCID:PMC9022993)

2021

Gundogdu, M., Tadayon, R., Salzano, G. , Shaw, G. S. and Walden, H. (2021) A mechanistic review of Parkin activation. Biochimica et Biophysica Acta. General Subjects, 1865(6), 129894. (doi: 10.1016/j.bbagen.2021.129894) (PMID:33753174)

Rennie, M. L. , Arkinson, C., Chaugule, V. K. , Toth, R. and Walden, H. (2021) Structural basis of FANCD2 deubiquitination by USP1-UAF1. Nature Structural and Molecular Biology, 28(4), pp. 356-364. (doi: 10.1038/s41594-021-00576-8) (PMID:33795880)

2020

Mitxitorena, I., Somma, D. , Mitchell, J. P., Lepistö, M., Tyrchan, C., Smith, E. L., Kiely, P. A., Walden, H. , Keeshan, K. and Carmody, R. J. (2020) The deubiquitinase USP7 uses a distinct ubiquitin-like domain to deubiquitinate NF-ĸB subunits. Journal of Biological Chemistry, 295(33), pp. 11754-11763. (doi: 10.1074/jbc.RA120.014113) (PMID:32587091) (PMCID:PMC7450122)

Rennie, M. L. , Lemonidis, K. , Arkinson, C., Chaugule, V. K. , Clarke, M. , Streetley, J. , Spagnolo, L. and Walden, H. (2020) Differential functions of FANCI and FANCD2 ubiquitination stabilize ID2 complex on DNA. EMBO Reports, 21(7), e50133. (doi: 10.15252/embr.202050133) (PMID:32510829) (PMCID:PMC7332966)

Frost, M. G., Mazloumi Aboukheili, A. M., Toth, R. and Walden, H. (2020) Characterisation of FANCL variants observed in patient cancer cells. Bioscience Reports, 40(6), 20191304. (doi: 10.1042/BSR20191304) (PMID:32420600) (PMCID:PMC7273913)

Rennie, M. L. , Chaugule, V. K. and Walden, H. (2020) Modes of allosteric regulation of the ubiquitination machinery. Current Opinion in Structural Biology, 62, pp. 189-196. (doi: 10.1016/j.sbi.2020.02.003) (PMID:32305021)

Chaugule, V. K., Arkinson, C., Rennie, M. L. , Kämäräinen, O., Toth, R. and Walden, H. (2020) Allosteric mechanism for site-specific ubiquitination of FANCD2. Nature Chemical Biology, 16, pp. 291-301. (doi: 10.1038/s41589-019-0426-z) (PMID:31873223)

2019

Gundogdu, M. and Walden, H. (2019) Structural basis of generic versus specific E2-RING E3 interactions in protein ubiquitination. Protein Science, 28(10), pp. 1758-1770. (doi: 10.1002/pro.3690) (PMID:31340062)

Chaugule, V. K., Arkinson, C., Toth, R. and Walden, H. (2019) Enzymatic preparation of monoubiquitinated FANCD2 and FANCI proteins. In: Hochstrasser, M. (ed.) Ubiquitin and Ubiquitin-like Protein Modifiers. Series: Methods in Enzymology, 618 (618). Elsevier, pp. 73-104. ISBN 9780128163597 (doi: 10.1016/bs.mie.2018.12.021)

2018

Condos, T. E.C., Dunkerley, K. M., Freeman, E. A., Barber, K. R., Aguirre, J. D., Chaugule, V. K., Xiao, Y., Konermann, L., Walden, H. and Shaw, G. S. (2018) Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation. EMBO Journal, e100014. (doi: 10.15252/embj.2018100014) (PMID:30446597)

Arkinson, C., Chaugule, V. K., Toth, R. and Walden, H. (2018) Specificity for deubiquitination of monoubiquitinated FANCD2 is driven by the N-terminus of USP1. Life Science Alliance, 1(5), e201800162. (doi: 10.26508/lsa.201800162) (PMID:30456385) (PMCID:PMC6238601)

Walden, H. and Rittinger, K. (2018) RBR ligase–mediated ubiquitin transfer: a tale with many twists and turns. Nature Structural and Molecular Biology, 25, pp. 440-445. (doi: 10.1038/s41594-018-0063-3) (PMID:29735995)

Bustos, F. et al. (2018) RNF12 X-linked intellectual disability mutations disrupt E3 ligase activity and neural differentiation. Cell Reports, 23(6), pp. 1599-1611. (doi: 10.1016/j.celrep.2018.04.022) (PMID:29742418) (PMCID:PMC5976579)

Arkinson, C. and Walden, H. (2018) Parkin function in Parkinson's disease. Science, 360(6386), pp. 267-268. (doi: 10.1126/science.aar6606) (PMID:29674580)

2017

Morreale, F. E., Testa, A., Chaugule, V. K. , Bortoluzzi, A., Ciulli, A. and Walden, H. (2017) Mind the metal: a fragment library-derived zinc impurity binds the E2 ubiquitin-conjugating enzyme Ube2T and induces structural rearrangements. Journal of Medicinal Chemistry, 60(19), pp. 8183-8191. (doi: 10.1021/acs.jmedchem.7b01071) (PMID:28933844)

Morreale, F. E., Bortoluzzi, A., Chaugule, V. K., Arkinson, C., Walden, H. and Ciulli, A. (2017) Allosteric targeting of the Fanconi anemia ubiquitin-conjugating enzyme Ube2T by fragment screening. Journal of Medicinal Chemistry, 60(9), pp. 4093-4098. (doi: 10.1021/acs.jmedchem.7b00147) (PMID:28437106) (PMCID:PMC5441753)

Kumar, A., Chaugule, V. K. , Condos, T. E.C., Barber, K. R., Johnson, C., Toth, R., Sundaramoorthy, R., Knebel, A., Shaw, G. S. and Walden, H. (2017) Parkin–phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity. Nature Structural and Molecular Biology, 24(5), pp. 475-483. (doi: 10.1038/nsmb.3400) (PMID:28414322) (PMCID:PMC5420311)

Walden, H. and Muqit, M. M.K. (2017) Ubiquitin and Parkinson's disease through the looking glass of genetics. Biochemical Journal, 474(9), pp. 1439-1451. (doi: 10.1042/BCJ20160498) (PMID:28408429) (PMCID:PMC5390927)

2016

Alpi, A. F., Chaugule, V. and Walden, H. (2016) Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3. Biochemical Journal, 473(20), pp. 3401-3419. (doi: 10.1042/BCJ20160028) (PMID:27729585) (PMCID:PMC5095918)

Morreale, F. E. and Walden, H. (2016) Types of ubiquitin ligases. Cell, 165(1), 248-248.e1. (doi: 10.1016/j.cell.2016.03.003) (PMID:27015313)

Chaugule, V. K. and Walden, H. (2016) Specificity and disease in the ubiquitin system. Biochemical Society Transactions, 44(1), pp. 212-227. (doi: 10.1042/BST20150209) (PMID:26862208) (PMCID:PMC5264512)

2015

Kumar, A. et al. (2015) Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. EMBO Journal, 34(20), pp. 2506-2521. (doi: 10.15252/embj.201592337) (PMID:26254304) (PMCID:PMC4609183)

Miles, J. A., Frost, M. G., Carroll, E., Rowe, M. L., Howard, M. J., Sidhu, A., Chaugule, V. K., Alpi, A. F. and Walden, H. (2015) The Fanconi Anemia DNA repair pathway is regulated by an interaction between ubiquitin and the E2-like fold domain of FANCL. Journal of Biological Chemistry, 290(34), pp. 20995-21006. (doi: 10.1074/jbc.M115.675835) (PMID:26149689) (PMCID:PMC4543658)

Kazlauskaite, A. et al. (2015) Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation. EMBO Reports, 16(8), pp. 939-954. (doi: 10.15252/embr.201540352) (PMID:26116755) (PMCID:PMC4552487)

2014

Walden, H. and Deans, A. J. (2014) The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder. Annual Review of Biophysics, 43(1), pp. 257-278. (doi: 10.1146/annurev-biophys-051013-022737) (PMID:24773018)

Spratt, D. E., Walden, H. and Shaw, G. S. (2014) RBR E3 ubiquitin ligases: new structures, new insights, new questions. Biochemical Journal, 458(3), pp. 421-437. (doi: 10.1042/BJ20140006) (PMID:24576094) (PMCID:PMC3940038)

Hodson, C., Purkiss, A., Miles, J. A. and Walden, H. (2014) Structure of the human FANCL RING-Ube2T complex reveals determinants of cognate E3-E2 selection. Structure, 22(2), pp. 337-344. (doi: 10.1016/j.str.2013.12.004) (PMID:24389026) (PMCID:PMC3979106)

2013

Spratt, D. E. et al. (2013) A molecular explanation for the recessive nature of parkin-linked Parkinson’s disease. Nature Communications, 4, 1983. (doi: 10.1038/ncomms2983) (PMID:23770917) (PMCID:PMC3709501)

2012

Walden, H. and Martinez-Torres, R. J. (2012) Regulation of Parkin E3 ubiquitin ligase activity. Cellular and Molecular Life Sciences, 69(18), pp. 3053-3067. (doi: 10.1007/s00018-012-0978-5) (PMID:22527713)

Kondapalli, C. et al. (2012) PINK1 is activated by mitochondrial membrane potential depolarization and stimulates Parkin E3 ligase activity by phosphorylating Serine 65. Open Biology, 2(5), 120080. (doi: 10.1098/rsob.120080) (PMID:22724072) (PMCID:PMC3376738)

Burchell, L., Chaugule, V. K. and Walden, H. (2012) Small, N-terminal tags activate Parkin E3 ubiquitin ligase activity by disrupting its autoinhibited conformation. PLoS ONE, 7(4), e34748. (doi: 10.1371/journal.pone.0034748) (PMID:22496854) (PMCID:PMC3319606)

Hodson, C. and Walden, H. (2012) Towards a molecular understanding of the Fanconi Anemia core complex. Anemia, 2012, 926787. (doi: 10.1155/2012/926787) (PMID:22675617) (PMCID:PMC3364535)

2011

Hodson, C., Cole, A. R., Lewis, L. P. C., Miles, J. A., Purkiss, A. and Walden, H. (2011) Structural analysis of human FANCL, the E3 ligase in the Fanconi anemia pathway. Journal of Biological Chemistry, 286(37), pp. 32628-32637. (doi: 10.1074/jbc.M111.244632) (PMID:21775430) (PMCID:PMC3173227)

Chaugule, V. K. , Burchell, L., Barber, K. R., Sidhu, A., Leslie, S. J., Shaw, G. s. and Walden, H. (2011) Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO Journal, 30(14), pp. 2853-2867. (doi: 10.1038/emboj.2011.204) (PMID:21694720) (PMCID:PMC3160258)

Marshall, K. E., Morris, K. L., Charlton, D., O’Reilly, N., Lewis, L., Walden, H. and Serpell, L. C. (2011) Hydrophobic, aromatic, and electrostatic interactions play a central role in amyloid fibril formation and stability. Biochemistry, 50(12), pp. 2061-2071. (doi: 10.1021/bi101936c) (PMID:21288003)

2010

Ulrich, H. D. and Walden, H. (2010) Ubiquitin signalling in DNA replication and repair. Nature Reviews Molecular Cell Biology, 11(7), pp. 479-489. (doi: 10.1038/nrm2921) (PMID:20551964)

Walden, H. (2010) Selenium incorporation using recombinant techniques. Acta Crystallographica. Section D: Biological Crystallography, 66(4), pp. 352-357. (doi: 10.1107/S0907444909038207) (PMID:20382987) (PMCID:PMC2852298)

Cole, A. R., Lewis, L. P.C. and Walden, H. (2010) The structure of the catalytic subunit FANCL of the Fanconi anemia core complex. Nature Structural and Molecular Biology, 17(3), pp. 294-298. (doi: 10.1038/nsmb.1759) (PMID:20154706) (PMCID:PMC2929457)

2009

Zhuang, M. et al. (2009) Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Molecular Cell, 36(1), pp. 39-50. (doi: 10.1016/j.molcel.2009.09.022) (PMID:19818708) (PMCID:PMC2847577)

2005

Duda, D. M., Walden, H. , Sfondouris, J. and Schulman, B. A. (2005) Structural analysis of Escherichia coli ThiF. Journal of Molecular Biology, 349(4), pp. 774-786. (doi: 10.1016/j.jmb.2005.04.011) (PMID:15896804)

Turner, S. J. et al. (2005) Lack of prominent peptide–major histocompatibility complex features limits repertoire diversity in virus-specific CD8+ T cell populations. Nature Immunology, 6(4), pp. 382-389. (doi: 10.1038/ni1175) (PMID:15735650)

2004

Theodossis, A., Walden, H. , Westwick, E. J., Connaris, H., Lamble, H. J., Hough, D. W., Danson, M. J. and Taylor, G. L. (2004) The structural basis for substrate promiscuity in 2-keto-3-deoxygluconate aldolase from the Entner-Doudoroff pathway in Sulfolobus solfataricus. Journal of Biological Chemistry, 279(42), pp. 43886-43892. (doi: 10.1074/jbc.M407702200) (PMID:15265860)

Walden, H. , Taylor, G. L., Lorentzen, E., Pohl, E., Lilie, H., Schramm, A., Knura, T., Stubbe, K., Tjaden, B. and Hensel, R. (2004) Structure and function of a regulated archaeal triosephosphate isomerase adapted to high temperature. Journal of Molecular Biology, 342(3), pp. 861-875. (doi: 10.1016/j.jmb.2004.07.067) (PMID:15342242)

Huang, D. T., Walden, H. , Duda, D. and Schulman, B. A. (2004) Ubiquitin-like protein activation. Oncogene, 23(11), pp. 1958-1971. (doi: 10.1038/sj.onc.1207393) (PMID:15021884)

2003

Walden, H. , Podgorski, M. S., Huang, D. T., Miller, D. W., Howard, R. J., Minor, D. L., Holton, J. M. and Schulman, B. A. (2003) The structure of the APPBP1-UBA3-NEDD8-ATP complex reveals the basis for selective ubiquitin-like protein activation by an E1. Molecular Cell, 12(6), pp. 1427-1437. (doi: 10.1016/S1097-2765(03)00452-0) (PMID:14690597)

Walden, H. , Podgorski, M. S. and Schulman, B. A. (2003) Insights into the ubiquitin transfer cascade from the structure of the activating enzyme for NEDD8. Nature, 422(6929), pp. 330-334. (doi: 10.1038/nature01456) (PMID:12646924)

2001

Walden, H. , Bell, G. S., Russell, R. J.M., Siebers, B., Hensel, R. and Taylor, G. L. (2001) Tiny TIM: a small, tetrameric, hyperthermostable triosephosphate isomerase. Journal of Molecular Biology, 306(4), pp. 745-757. (doi: 10.1006/jmbi.2000.4433) (PMID:11243785)

This list was generated on Wed Nov 20 19:08:08 2024 GMT.

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