研究领域
Structural biology of extracellular matrix
Extracellular matrix (ECM) is assembled from secreted macromolecules by a combination of spontaneous and cell-assisted processes. Cells interact with ECM using a variety of membrane-spanning receptors, and these interactions critically regulate cell behaviour. Many human diseases are the result of faulty ECM assembly or cell-matrix communication. Defective adhesion of skeletal muscle cells to ECM, for instance, causes muscular dystrophy, and the loss of regulation by ECM is a key step in the progression of many cancers.
The broad aim of our research programme is to understand ECM assembly and signalling at the molecular level. We determine atomic structures of ECM proteins using X-ray crystallography and investigate their interactions using a variety of biochemical and biophysical techniques.
Laminins are major constituents of basement membranes, the evolutionarily most ancient type of ECM. Laminins are heterotrimers that polymerise spontaneously at body temperature (Hohenester and Yurchenco, 2013):
3-Arm
We determined the structures of the N-terminal LN domains that mediate laminin polymerisation and identified residues that are critical for this process (Hussain et al, 2011; Carafoli et al, 2012; Purvis and Hohenester, 2012).
The laminin network is anchored to the plasma membrane by interactions of the C-terminal LG domains with cellular receptors, such as integrins and dystroglycan. In 1999, we proposed that some LG domains may function as Ca2+-dependent lectins for the then uncharacterised carbohydrate modification of alpha-dystroglycan (Hohenester et al, 1999). In collaboration with Kevin Campbell (University of Iowa), we recently elucidated the atomic details of this important protein-carbohydrate interaction, which is compromised in a number of severe muscular dystrophies (Briggs et al, 2016):
Briggs
Collagens are best known as the major structural proteins of vertebrates. However, they also serve as ligands of two unusual receptor tyrosine kinases, DDR1 and DDR2, which are implicated in fibrotic diseases and many cancers. In collaboration with Birgit Leitinger (National Heart and Lung Institute), we defined the structural basis of sequence-specific collagen recognition by DDRs (Carafoli et al, 2009) and determined the structure of the complete DDR ectodomain (Carafoli et al, 2012).
The degradation of collagens is carried out by matrix metalloproteinases (MMPs). In collaboration with Hideaki Nagase (Kennedy Institute of Rheumatology) and Richard Farndale (University of Cambridge), we determined the long elusive structure of MMP-1 bound to a triple-helical collagen-like peptide (Manka et al, 2012). More recently, we determined the structure of an endocytic receptor (Endo180) that clears the collagen fragments generated by MMPs (Paracuellos et al, 2015).
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Ahmed YA, Yates EA, Moss DJ, Loeven MA, Hussain S-A, Hohenester E, Turnbull JE, Powell AKet al., 2016, Panels of chemically-modified heparin polysaccharides and natural heparan sulfate saccharides both exhibit differences in binding to Slit and Robo, as well as variation between protein binding and cellular activity, MOLECULAR BIOSYSTEMS, Vol: 12, Pages: 3166-3175, ISSN: 1742-206X
Briggs DC, Yoshida-Moriguchi T, Zheng T, Venzke D, Anderson ME, Strazzulli A, Moracci M, Yu L, Hohenester E, Campbell KPet al., 2016, Structural basis of laminin binding to the LARGE glycans on dystroglycan, NATURE CHEMICAL BIOLOGY, Vol: 12, Pages: 810-+, ISSN: 1552-4450
Pulido D, Briggs DC, Hua J, Hohenester Eet al., 2016, Crystallographic analysis of the laminin β2 short arm reveals how the LF domain is inserted into a regular array of LE domains, Matrix Biology, ISSN: 1569-1802
Paracuellos P, Briggs DC, Carafoli F, Loncar T, Hohenester Eet al., 2015, Insights into Collagen Uptake by C-type Mannose Receptors from the Crystal Structure of Endo180 Domains 1-4, STRUCTURE, Vol: 23, Pages: 2133-2142, ISSN: 0969-2126
Hohenester E, 2014, Signalling complexes at the cell-matrix interface, CURRENT OPINION IN STRUCTURAL BIOLOGY, Vol: 29, Pages: 10-16, ISSN: 0959-440X
Horejs C-M, Serio A, Purvis A, Gormley AJ, Bertazzo S, Poliniewicz A, Wang AJ, DiMaggio P, Hohenester E, Stevens MMet al., 2014, Biologically-active laminin-111 fragment that modulates the epithelial-to-mesenchymal transition in embryonic stem cells, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 111, Pages: 5908-5913, ISSN: 0027-8424
Riese SB, Kuehne C, Tedder TF, Hallmann R, Hohenester E, Buscher Ket al., 2014, Heterotropic Modulation of Selectin Affinity by Allosteric Antibodies Affects Leukocyte Rolling, JOURNAL OF IMMUNOLOGY, Vol: 192, Pages: 1862-1869, ISSN: 0022-1767
Xu H, Abe T, Liu JKH, Zalivina I, Hohenester E, Leitinger Bet al., 2014, Normal Activation of Discoidin Domain Receptor 1 Mutants with Disulfide Cross-links, Insertions, or Deletions in the Extracellular Juxtamembrane Region, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 13565-13574, ISSN: 0021-9258
Zelina P, Blockus H, Zagar Y, Peres A, Friocourt F, Wu Z, Rama N, Fouquet C, Hohenester E, Tessier-Lavigne M, Schweitzer J, Crollius HR, Chedotal Aet al., 2014, Signaling Switch of the Axon Guidance Receptor Robo3 during Vertebrate Evolution, NEURON, Vol: 84, Pages: 1258-1272, ISSN: 0896-6273
Carafoli F, Hamaia SW, Bihan D, Hohenester E, Farndale RWet al., 2013, An Activating Mutation Reveals a Second Binding Mode of the Integrin alpha 2 I Domain to the GFOGER Motif in Collagens, PLOS ONE, Vol: 8, ISSN: 1932-6203
Carafoli F, Hohenester E, 2013, Collagen recognition and transmembrane signalling by discoidin domain receptors, BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, Vol: 1834, Pages: 2187-2194, ISSN: 1570-9639
Hohenester E, Yurchenco PD, 2013, Laminins in basement membrane assembly, CELL ADHESION & MIGRATION, Vol: 7, Pages: 56-63, ISSN: 1933-6918
Horejs C, Bertazzo S, Hohenester E, Stevens Met al., 2013, The cleavage of Laminin-111 by MMP-2 affects early differentiation of murine ESCs and iPS cells, 38th Congress of the Federation-of-European-Biochemical-Societies (FEBS), Publisher: WILEY-BLACKWELL, Pages: 446-446, ISSN: 1742-464X
Islam M, Gor J, Perkins SJ, Ishikawa Y, Baechinger HP, Hohenester Eet al., 2013, The Concave Face of Decorin Mediates Reversible Dimerization and Collagen Binding, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 288, Pages: 35526-35533, ISSN: 0021-9258
Yip GMS, Chen Z-W, Edge CJ, Smith EH, Dickinson R, Hohenester E, Townsend RR, Fuchs K, Sieghart W, Evers AS, Franks NPet al., 2013, A propofol binding site on mammalian GABA(A) receptors identified by photolabeling, NATURE CHEMICAL BIOLOGY, Vol: 9, Pages: 715-+, ISSN: 1552-4450
Carafoli F, Hussain S-A, Hohenester E, 2012, Crystal Structures of the Network-Forming Short-Arm Tips of the Laminin beta 1 and gamma 1 Chains, PLOS ONE, Vol: 7, ISSN: 1932-6203
Carafoli F, Mayer MC, Shiraishi K, Pecheva MA, Chan LY, Nan R, Leitinger B, Hohenester Eet al., 2012, Structure of the Discoidin Domain Receptor 1 Extracellular Region Bound to an Inhibitory Fab Fragment Reveals Features Important for Signaling, STRUCTURE, Vol: 20, Pages: 688-697, ISSN: 0969-2126
Manka SW, Carafoli F, Visse R, Bihan D, Raynal N, Farndale RW, Murphy G, Enghild JJ, Hohenester E, Nagase Het al., 2012, Structural insights into triple-helical collagen cleavage by matrix metalloproteinase 1, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 12461-12466, ISSN: 0027-8424
Purvis A, Hohenester E, 2012, Laminin Network Formation Studied by Reconstitution of Ternary Nodes in Solution, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 44270-44277, ISSN: 0021-9258
Hohenester E, 2011, Tackling the Legs of Mannan-Binding Lectin, STRUCTURE, Vol: 19, Pages: 1538-1540, ISSN: 0969-2126
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