The Laman Lab's mission is to understand and devise novel treatments for diseases caused by deregulation of ubiquitin ligases.
Research in our lab focuses on the study of ubiquitin ligases. They are remarkably multi-functional proteins and touch on aspects of biology ranging from development and regulation of the cell cycle to the immune system and cell signalling. Given such central roles, their malfunctioning is linked with many pathologies, such as cancer, neurodegenerative, and infectious diseases. Our research has branched into many diverse areas, including developing novel therapeutics against ubiquitin ligases, but our focus on these enigmatic enzymes is the common link for our group.
Our laboratory is based on the Downing Site in Tennis Court Road in central Cambridge with access to the nearby Institutes and Departments in the School of Biological Sciences, the city centre and the Colleges.
+44 (0)1223 333722
Department of Pathology,
Division of Cellular and Molecular Pathology,
University of Cambridge Tennis Court Road
Cambridge CB2 1QP
Cambridge CB2 1TL
Ubiquitin ligases are enzymes that decorate proteins in the cell with ubiquitin, a relatively large (76aa) peptide. This modification with ubiquitin on a protein can signal many different things to the target substrate, A well-described effect brought about by ubiquitination is that it changes a protein's stability, but other effects include changes to localisation, intracellular trafficking, binding partners, and function. My laboratory is particularly intrigued by these 'alternate' ubiquitin-mediated signals. We are also interested in ubiquitin signalling within different cellular contexts, as we have discovered ubiquitin networks vary from tissue to tissue and use mouse models to study the molecular basis for this. We want to understand the dynamic nature and complexity of ubiquitin signalling, and invent novel therapeutics exploiting ubiquitin ligase enzymology and their critically regulated pathways.
The biology of Fbxo7/PARK15: from anaemia to cancer to Parkinson's disease.
In 1997, we cloned the F-box protein, Fbxo7, as an interacting partner for a herpesvirus-encoded viral cyclin. We have since created multiple mouse models that are deficient in the expression of Fbxo7 either in the whole mouse or in specific tissues. We investigate the numerous disease, including anaemia and cancer, seen in multiple tissues, ranging from both B and T lymphocytes to red blood cells. In 2008. mutations in Fbxo7 were discovered to be associated with idiopathic and early onset forms of Parkinson's disease. We also investigate the loss of its expression in dopaminergic neurons, the cells that are lost in this disease. We are investigating the molecular basis for the different pathways regulated by Fbxo7 that cause these pathologies in various cell types.
Targeting ubiquitin ligases and ubiquitinated proteins with novel biotherapeutic approaches.
The discovery of camelid-derived antibodies known as nanobodies offers researchers all the specificity and affinities of conventional antibodies in a compact, highly-stable domain, known as a nanobody. We use nanobodies to define and test the functional significance of interactions between ubiquitin ligases and their substrates. We collaborate with Serge Muyldermans to produce nanobodies.
We also are investigating the possibility of specifically interfering with the capacity of ubiquitin ligases to modify their substrates. Based on structural information, we collaborate with Laura Itzhaki and David Spring in the production of stapled peptides that mimic the conformation of docked substrates in ubiquitin ligases and test the biochemical and cellular effects of stapled peptides on the ubiquitin ligases.
Deregulated SCF networks in epithelial cancers.
We are investigating the consequences of the rearrangement of two F-box genes in breast cancer. We are doing a biochemical analysis of the effect of the mutations on the ligases and on the pathways that they regulate using proteome wide approaches, including protein arrays, mass spectrometry, and yeast two hybrid screens. Specific substrates and the critical pathways that are deregulated are being defined, and their role in oncogeneisis studied.
Loss of FBXO7 results in a Parkinson’s-like dopaminergic degeneration via an RPL23-MDM2-TP53 pathway. J. Path. Stott SRW*, Randle SJ*, al Rawi S, Rowicka PA, Harris R, Mason B, Xia J, Dalley, JW, Barker RA, Laman H. 2019 May. https://doi.org/10.1002/path.5312
Structure and function of Fbxo7/PARK15 in Parkinson's disease. Randle SJ, Laman H. Curr Protein Pept Sci. 2017;18(7):715-724. . Link. PDF
Gsk3β and Tomm20 are substrates of the SCF-Fbxo7/PARK15 ubiquitin ligase associated with Parkinson's disease. Teixeira FR^, Randle SJ^, Patel SP^, Mevissen TE, Zenkeviciute G, Koide T, Komander D, Laman H. Biochem J. 2016 Oct 15;473(20):3563-3580. ^First author. Link. PDF. Supp.
The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Burchell VS^, Nelson DE^, Sanchez-Martinez A^, Delgado-Camprubi M, Ivatt RM, Pogson JH, Randle SJ, Wray S, Lewis PA, Houlden H, Abramov AY, Hardy J, Wood NW, Whitworth AJ*, Laman H*, Plun-Favreau H*. Nat Neurosci. 2013 Sep;16(9):1257-65. ^First author; *Senior corresponding author. Link. PDF.
Identification of F-box only protein 7 as a negative regulator of NF-kappaB signalling. Kuiken HJ, Egan DA, Laman H, Bernards R, Beijersbergen RL, Dirac AM. J Cell Mol Med. 2012 Sep;16(9):2140-9. Link. PDF
Exploring the interaction between siRNA and the SMoC biomolecule transporters: implications for small molecule-mediated delivery of siRNA. Gooding M, Tudzarova S, Worthington RJ, Kingsbury SR, Rebstock AS, Dube H, Simone MI, Visintin C, Lagos D, Quesada JM, Laman H, Boshoff C, Williams GH, Stoeber K, Selwood DL. Chem Biol Drug Des. 2012 Jan;79(1):9-21. Link. PDF
Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis. Lomonosov M, Meziane el K, Ye H, Nelson DE, Randle SJ, Laman H. PLoS One. 2011;6(6):e21165. Link. PDF
Knockdown of Fbxo7 reveals its regulatory role in proliferation and differentiation of haematopoietic precursor cells. Meziane el K^, Randle SJ^, Nelson DE, Lomonosov M, Laman H. J Cell Sci. 2011 Jul 1;124(Pt 13):2175-86. ^First author. Link. PDF
Structure of a conserved dimerization domain within the F-box protein Fbxo7 and the PI31 proteasome inhibitor. Kirk R, Laman H, Knowles PP, Murray-Rust J, Lomonosov M, Meziane el K, McDonald NQ. J Biol Chem. 2008 Aug 8;283(32):22325-35. Link. PDF
Small-molecule mimics of an alpha-helix for efficient transport of proteins into cells.Okuyama M^, Laman H^, Kingsbury SR^, Visintin C, Leo E, Eward KL, Stoeber K, Boshoff C, Williams GH, Selwood DL. ^First author. Nat Methods. 2007 Feb;4(2):153-9. Link. PDF
Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6. Laman H, Funes JM, Ye H, Henderson S, Galinanes-Garcia L, Hara E, Knowles P, McDonald N, Boshoff C. EMBO J. 2005 Sep 7;24(17):3104-16. Link. PDF
RNA interference: a potential tool against Kaposi's sarcoma-associated herpesvirus. Godfrey A, Laman H, Boshoff C. Curr Opin Infect Dis. 2003 Dec;16(6):593-600. Link.
Cyclin-mediated export of human Orc1. Laman H, Peters G, Jones N. Exp Cell Res. 2001 Dec 10;271(2):230-7. Link. PDF
Disturbance of normal cell cycle progression enhances the establishment of transcriptional silencing in Saccharomyces cerevisiae. Laman H, Balderes D, Shore D. Mol Cell Biol. 1995 Jul;15(7):3608-17. Link. PDF
Identification of a nitrogen-regulated promoter controlling expression of Klebsiella pneumoniae urease genes. Collins CM, Gutman DM, Laman H. Mol Microbiol. 1993 Apr;8(1):187-98. Link.
Dr. Heike Laman
Heike Laman was awarded her B.Sc. from the University of Miami in 1990, majoring in Microbiology & Immunology with a double minor in Chemistry and Biology. She graduated cum laude, with General Honors, and was a elected a member of Phi Beta Kappa and Phi Beta Phi.
Prior to starting her PhD studies, she worked as a research assistant with Dr. Carleen Collins. Here she sequenced the entire urease operon in Klebsiella pneumoniae and discovered the promoter elements controlling its expression.
She earned her MA, MPhil and Ph.D. degrees from Columbia University in 1992, 1994, and 1997, respectively. Her graduate studies were supervised by Dr. David Shore at Columbia University in the Department of Microbiology & Immunology, researching heterchromatin assembly in Saccharomyces cerevisiae.
Dr. Laman emigrated to the United Kingdom in 1997 to undertake post-doctoral research. She was awarded a Research Fellowship from the Imperial Cancer Research Fund in London to work on virally-encoded cyclins with Dr. Nic Jones from 1997-1999, and when he moved to Manchester, she continued her research in the Cell Cycle Regulation laboratory of Dr. Gordon Peters, from 1999-2001. She was awarded a project grant by the Association for International Cancer Research working as a Senior Research Fellow in the Viral Oncology laboratory of Dr. Chris Boshoff at the Wolfson Institute for Biomedical Research at University College London.
In 2005, Dr. Laman was awarded a Research Fellowship and appointed as a Senior Research Associate in the Department of Pathology at the University of Cambridge. She became a University Lecturer in 2007, and was elected to the Fellowship of Clare College in 2014.
We are always seeking talented, enthusiastic, and curious minds to join our group. Post-doctoral candidates are encouraged to get in touch, sending your CV, to enquire about possibilities,
Lorna joined the lab in October 2018 to start a BBSRC funded PhD investigating the post-translational control of mitochondria by Fbxo7 in Parkinson’s disease. She graduated in 2018 from the University of Glasgow with a first class MSci degree with honours in Biochemistry. During the final year of her degree she studied mitochondrial biology and completed a research project studying the role of the thioredoxin redox system within the mitochondrial intermembrane space. As part of her degree she also undertook an industrial placement year at the pharmaceutical company GlaxoSmithKline in which she validated a new transposase-based transfection mechanism for use in the generation of stable cell lines.
Linda joined the lab in September 2018 for her MPhil to work with nanobody technology. Grown up in Shanghai, she had her first cell and molecular biology laboratory experience at Shanghai Jiao Tong University, where she did drug screening on NB4 acute promyelocytic leukemia (APL) cell line and drug resistant NB4-R1 APL cell line, and published the structure of kallistatin in Acta Crystallographica. During her Natural Sciences and Biochemistry undergraduate studies at University of Cambridge, she interned in Stephen Cusack’s lab at European Molecular Biology Laboratory in Grenoble doing purifications of Influenza B strain proteins, in Qiaoran Xi’s Group at Beijing Tsinghua University working on experiments with in vivo models and embryonic stem cells, and in David Barford’s group at MRC Laboratory of Molecular Biology for recombinant cloning of large chromatin associated complex in mammalian systems. She also interned at Allergan in Liverpool and carried out quantitative assays on residual host cell DNA and viral genomes.
Sara al Rawi
Born in Paris, Sara joined the lab in 2018 to start a Parkinson's UK-funded research project investigating the neuroprotective roles of Fbxo7 with a focus on an early stages of Parkinson's disease. Previously, Sara obtained a Master degree in cellular and molecular biology with a specialization in proteomics from the Pierre and Marie Curie University, in Paris. After being awarded her degree, Sara began working as a research assistant to investigate how sperm derived mitochondria are degraded in the early embryo using C. elegans as a model. This work led to the discovery of the autophagy pathway in this specific degradation event. Sara was awarded an AXA-Academie des Sciences award from the French Science academy for her work. Her PhD research was under the supervision of Dr Vincent Galy at the Pierre and Marie Curie University and focussed on discovering how sperm-derived mitochondria are specifically recognized and targeted by the autophagy machinery.
Rebecca joined the lab in October 2017 to start a PhD exploring the role of Fbxo7 on T cell metabolism and function. She graduated from the University of Warwick with a first class BSc (Hons) degree in Biochemistry, with an Industrial Year spent at GlaxoSmithKline investigating dendritic cell maturation using flow cytometry and cytokine assays. Prior to her PhD, she worked on the AstraZeneca IMED graduate programme for 2 years, completing rotation projects across early-stage drug discovery. Specifically, she generated ctDNA reference standards to evaluate companion diagnostic technologies, developed high-throughput CETSA assays to measure in-cell target engagement, and built an immune antibody library to isolate high-affinity monoclonal antibodies.
Born in Scarborough, North Yorkshire, Bethany graduated from The University of Manchester in 2015 with a Bachelor of Science (Hons) in Biomedical Sciences with Industrial/Professional Experience. Bethany spent her placement year at The University of Copenhagen, Denmark, where she carried out a research project studying chromatin dynamics in fission yeast. Her final year undergraduate research project focused on the role of micro-RNAs in the maturation and activation of macrophages in diabetes. Bethany joined the lab in January 2016 to begin a four year PhD looking at F-box proteins and their role in breast cancer.
Grasilda is a 4th year PhD student working on an interdisciplinary project funded by Cambridge Cancer Centre. She is developing constrained peptides to target an oncogenic E3 ligase and her work is done in close collaboration with Dr Itzhaki in Pharmacology department. Before joining the lab, Grasilda graduated from the University of Edinburgh with a First Class masters degree with honours in Medicinal and Biological Chemistry. She spent her placement year at European Molecular Biology Laboratory (Hamburg) in Matthias Wilmanns' lab working on structural and functional analysis of Type VII secretion system proteins. During her time in Edinburgh Grasilda was awarded Amgen and BBSRC scholarships to carry out summer projects in Karolinska Institute and the University of Oxford. In her free time Grasilda enjoys the great outdoors and goes hiking around UK and Europe.
Past Lab Members
Prof. Roger Barker: Department of Clinical Neurosciences, University of Cambridge, Link.
Dr. Erwin de Genst: AstraZeneca, Discovery Science, AstraZeneca. Link.
Dr. Paul Edwards: Department of Pathology, University of Cambridge. Link.
Prof Gerard Evan: Department of Biochemistry, University of Cambridge. Link.
Dr. Laura Itzhaki: Department of Pharmacology, University of Cambridge. Link.
Prof. Kathryn Lilley: Department of Biochemistry, University of Cambridge. Link.
Dr. David Komander: Laboratory of Molecular Biology, Cambridge. Link.
Prof. Serge Muyldermans: Vrije Universiteit Brussel, Belgium. Link.
Dr. David Spring: Department of Chemistry, University of Cambridge. Link.
Prof Felipe Teixeira: Department of Genetics and Evolution, Universidad Federal Sao Carlos. Link.
Prof Massimo Zeviani: Mitochondrial Biology Unit, Cambridge Institute for Biomedical Research. Link.
University of Cambridge
Department of Pathology
Tennis Court Road
Cambridge CB2 1QP