Timothy A. Springer, PhD

Boston Children's Hospital

Boston Children's Hospital
Phone: (617) 713-8200
Fax: (617) 713-8232


springer@crystal.harvard.edu

Timothy A. Springer, PhD

Boston Children's Hospital

EDUCATIONAL TITLES

  • Latham Family Professor of Biological Chemistry and Molecular Pharmacology, Biological Chemistry and Molecular Pharmacology, Harvard Medical School
  • Latham Family Professor of Pathology, IDI, Boston Children's Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

This laboratory has discovered and works on families of adhesion and chemoattractant receptors that regulate specific cell interactions, localization, migration, and differentiation of cells of the immune system. The importance of integrins on leukocytes in vivo has been demonstrated by an inherited disease, leukocyte adhesion deficiency, in which mutations affect the common b subunit that associates with three different a subunits to form ab heterodimers. The leukocyte integrins LFA-1 and Mac-1 bind to members of the immunoglobulin supergene family called intercellular adhesion molecules (ICAMs).

The adhesiveness of LFA-1 for ICAM-1 is regulated by T cell activation by antigen; thus, LFA-1 acts as an adhesion servomotor under the control of the T cell recptor for antigen. High avidity of LFA-1 is transient, providing a mechanism for de-adhesion. Truncation of the cloned b subunit cytoplasmic domain abrogates the high avidity state. We have predicted the structure of several integrin domains, including a G protein-like b-propeller domian. We are working on the structure of integrins to obtain a molecular model of how signals that regulate ligand binding and cell proliferation are propagated by conformational changes.

Mutagenesis studies are defining the regions in the extracellular domains of integrins and ICAMs involved in ligand binding. We have determined the crystal structure of ICAM-1, ICAM-2, and MAdCAM-1 and are using this information to guide mutagenesis to study their binding sites for integrins. ICAM-1 is subverted as a receptor by rhinoviruses, and novel chimaeric molecules are being constructed to neutralize rhinoviruses, and to understand how receptor binding leads to host cell penetration.

Selectins that bind carbohydrate ligands mediate the initial tethering of flowing lekocytes to the vessel wall and subsequent rolling. The a4b1 and a4b7 integrins can also mediate rolling by binding VCAM-1 on MAdCAM-1. We are examining leukocyte interactions with purified adhesion molecules, or with a monolayer of platelets or endothelial cells, in a flow system at physiologic shear stress. The biophysics that regulate rolling are being explored.

Work on chemoattractants and their receptors focuses on their function in lymphocyte trafficking, as HIV co-receptors, and structure.

A multi-step model suggests specificity of leukocyte trafficking is due to combinatorial diversity in signals from selectins, chemoattractants, and integrin ligands that are displayed on vascular endothelium.

Publications

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  • Mi LZ, Brown CT, Gao Y, Tian Y, Le VQ, Walz T, Springer TA. Structure of bone morphogenetic protein 9 procomplex. Proc Natl Acad Sci U S A 2015; 112:3710-5. PubMed
  • Kollmann CS, Bai X, Tsai CH, Yang H, Lind KE, Skinner SR, Zhu Z, Israel DI, Cuozzo JW, Morgan BA, Yuki K, Xie C, Springer TA, Shimaoka M, Evindar G. Application of encoded library technology (ELT) to a protein-protein interaction target: Discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists. Bioorg Med Chem 2014; 22:2353-65. PubMed
  • Sen M, Yuki K, Springer TA. An internal ligand-bound, metastable state of a leukocyte integrin, 留X硫2. J Cell Biol 2014; 203:629-42. PubMed
  • Yu Y, Schürpf T, Springer TA. How natalizumab binds and antagonizes 留4 integrins. J Biol Chem 2013; 288:32314-25. PubMed
  • Zhu J, Zhu J, Springer TA. Complete integrin headpiece opening in eight steps. J Cell Biol 2013; 201:1053-68. PubMed
  • Martinelli R, Kamei M, Sage PT, Massol R, Varghese L, Sciuto T, Toporsian M, Dvorak AM, Kirchhausen T, Springer TA, Carman CV. Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds. J Cell Biol 2013; 201:449-65. PubMed
  • Yu Y, Zhu J, Huang PS, Wang JH, Pullen N, Springer TA. Domain 1 of mucosal addressin cell adhesion molecule has an I1-set fold and a flexible integrin-binding loop. J Biol Chem 2013; 288:6284-94. PubMed
  • Xu AJ, Springer TA. Mechanisms by which von Willebrand disease mutations destabilize the A2 domain. J Biol Chem 2013; 288:6317-24. PubMed
  • Dong X, Mi LZ, Zhu J, Wang W, Hu P, Luo BH, Springer TA. 留(V)硫(3) Integrin Crystal Structures and Their Functional Implications. Biochemistry 2012; 51:8814-28. PubMed
  • Lu C, Mi LZ, Schürpf T, Walz T, Springer TA. Mechanisms for Kinase-mediated Dimerization of the Epidermal Growth Factor Receptor. J Biol Chem 2012; 287:38244-53. PubMed
  • Schürpf T, Chen Q, Liu JH, Wang R, Springer TA, Wang JH. The RGD finger of Del-1 is a unique structural feature critical for integrin binding. FASEB J. 2012; 26:3412-20. PubMed
  • Zhou YF, Eng ET, Zhu J, Lu C, Walz T, Springer TA. Sequence and structure relationships within von Willebrand factor. Blood 2012; 120:449-58. PubMed
  • Kang S, Kim CU, Gu X, Owens RM, van Rijn SJ, Boonyaleepun V, Mao Y, Springer TA, Jin MM. Complex structure of engineered modular domains defining molecular interaction between ICAM-1 and integrin LFA-1. PLoS ONE 2012; 7:e44124. PubMed
  • Zhou M, Dong X, Baldauf C, Chen H, Zhou Y, Springer TA, Luo X, Zhong C, Gräter F, Ding J. A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13. Blood 2011. PubMed
  • Wang W, Zhu J, Springer TA, Luo BH. Tests of integrin transmembrane domain homo-oligomerization during integrin ligand binding and signaling. J Biol Chem 2011; 286:1860-7. PubMed
  • Pan Y, Zhang K, Qi J, Yue J, Springer TA, Chen J. Cation-pi interaction regulates ligand-binding affinity and signaling of integrin alpha4beta7. Proc Natl Acad Sci U S A 2011; 107:21388-93. PubMed
  • Zhu J, Zhu J, Negri A, Provasi D, Filizola M, Coller BS, Springer TA. The closed headpiece of integrin {alpha}IIb{beta}3 and its complex with an {alpha}IIb{beta}3-specific antagonist that does not induce opening. Blood 2010; 116:5050-9. PubMed
  • Lu C, Mi LZ, Grey MJ, Zhu J, Graef E, Yokoyama S, Springer TA. Structural Evidence for Loose Linkage between Ligand Binding and Kinase Activation in the Epidermal Growth Factor Receptor. Mol Cell Biol 2010; 30:5432-43. PubMed
  • Smagghe BJ, Huang PS, Ban YE, Baker D, Springer TA. Modulation of integrin activation by an entropic spring in the {beta}-knee. J Biol Chem 2010; 285:32954-66. PubMed
  • Kim J, Zhang CZ, Zhang X, Springer TA. A mechanically stabilized receptor-ligand flex-bond important in the vasculature. Nature 2010; 466:992-5. PubMed
  • Chen X, Xie C, Nishida N, Li Z, Walz T, Springer TA. Requirement of open headpiece conformation for activation of leukocyte integrin alphaXbeta2. Proc Natl Acad Sci U S A 2010; 107:14727-32. PubMed
  • Owens RM, Gu X, Shin M, Springer TA, Jin MM. Engineering of single Ig superfamily domain of ICAM-1 for native fold and function. J Biol Chem 2010; 285:15906-15. PubMed
  • Wolf JC, Lutz I, Kloas W, Springer TA, Holden LR, Krueger HO, Hosmer AJ. Effects of 17 beta-estradiol exposure on Xenopus laevis gonadal histopathology. Environ Toxicol Chem 2010; 29:1091-105. PubMed
  • Xie C, Zhu J, Chen X, Mi L, Nishida N, Springer TA. Structure of an integrin with an alphaI domain, complement receptor type 4. EMBO J 2010; 29:666-79. PubMed
  • Zhang X, Halvorsen K, Zhang CZ, Wong WP, Springer TA. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science 2009; 324:1330-4. PubMed
  • Zhu J,Luo BH,Barth P,Schonbrun J,Baker D,Springer TA. The structure of a receptor with two associating transmembrane domains on the cell surface: integrin alphaIIbbeta3. Mol Cell 2009; 34:234-49. PubMed
  • Waldron TT,Springer TA. Transmission of allostery through the lectin domain in selectin-mediated cell adhesion. Proc Natl Acad Sci U S A 2009; 106:85-90. PubMed
  • Carman CV,Springer TA. Trans-cellular migration: cell-cell contacts get intimate. Curr Opin Cell Biol 2008; 20:533-40. PubMed
  • Lutz I, Kloas W, Springer TA, Holden LR, Wolf JC, Krueger HO, Hosmer AJ. Development, standardization and refinement of procedures for evaluating effects of endocrine active compounds on development and sexual differentiation of Xenopus laevis. Anal Bioanal Chem 2008; 390:2031-48. PubMed
  • Morin NA, Oakes PW, Hyun YM, Lee D, Chin YE, King MR, Springer TA, Shimaoka M, Tang JX, Reichner JS, Kim M. Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration. J Exp Med 2008; 205:195-205. PubMed
  • Vorup-Jensen T, Chi L, Gjelstrup LC, Jensen UB, Jewett CA, Xie C, Shimaoka M, Linhardt RJ, Springer TA. Binding between the integrin alphaXbeta2 (CD11c/CD18) and heparin. J Biol Chem 2007; 282:30869-77. PubMed
  • Zhu J, Carman CV, Kim M, Shimaoka M, Springer TA, Luo BH. Requirement of alpha and beta subunit transmembrane helix separation for integrin outside-in signaling. Blood 2007; 110:2475-83. PubMed
  • Chen X, Kim TD, Carman CV, Mi LZ, Song G, Springer TA. Structural plasticity in Ig superfamily domain 4 of ICAM-1 mediates cell surface dimerization. Proc Natl Acad Sci U S A 2007; 104:15358-63. PubMed
  • Bonasio R, Carman CV, Kim E, Sage PT, Love KR, Mempel TR, Springer TA, von Andrian UH. Specific and covalent labeling of a membrane protein with organic fluorochromes and quantum dots. Proc Natl Acad Sci U S A 2007; 104:14753-8. PubMed
  • Vorup-Jensen T, Waldron TT, Astrof N, Shimaoka M, Springer TA. The connection between metal ion affinity and ligand affinity in integrin I domains. Biochim Biophys Acta 2007; 1774:1148-55. PubMed
  • Carman CV, Sage PT, Sciuto TE, de la Fuente MA, Geha RS, Ochs HD, Dvorak HF, Dvorak AM, Springer TA. Transcellular diapedesis is initiated by invasive podosomes. Immunity 2007; 26:784-97. PubMed
  • Phan UT, Waldron TT, Springer TA. Remodeling of the lectin-EGF-like domain interface in P- and L-selectin increases adhesiveness and shear resistance under hydrodynamic force. Nat Immunol 2006; 7:883-9. PubMed
  • Artoni A, Li J, Mitchell B, Ruan J, Takagi J, Springer TA, French DL, Coller BS. Integrin {beta}3 regions controlling binding of murine mAb 7E3: Implications for the mechanism of integrin {alpha}IIb{beta}3 activation. Proc Natl Acad Sci U S A 2004; 101:13114-20. PubMed
  • Luo BH, Strokovich K, Walz T, Springer TA, Takagi J. Allosteric beta1 integrin antibodies that stabilize the low affinity state by preventing the swing-out of the hybrid domain. J Biol Chem 2004; 279:27466-71. PubMed
  • Luo BH, Springer TA, Takagi J. A specific interface between integrin transmembrane helices and affinity for ligand. PLoS Biol 2004; 2:776-86. PubMed
  • Yang Y, Jun CD, Liu JH, Zhang R, Joachimiak A, Springer TA, Wang JH. Structural basis for dimerization of ICAM-1 on the cell surface. Mol Cell 2004; 14:269-76. PubMed
  • Salas A, Shimaoka M, Kogan AN, Harwood C, von Andrian UH, Springer TA. Rolling adhesion through an extended conformation of integrin alphaLbeta2 and relation to alpha I and beta I-like domain interaction. Immunity 2004; 20:393-406. PubMed
  • Culi J, Springer TA, Mann RS. Boca-dependent maturation of beta-propeller/EGF modules in low-density lipoprotein receptor proteins. EMBO J 2004; 23:1372-80. PubMed
  • Luo BH, Takagi J, Springer TA. Locking the beta3 integrin I-like domain into high and low affinity conformations with disulfides. J Biol Chem 2003; 279:10215-21. PubMed
  • Yang W, Shimaoka M, Salas A, Takagi J, Springer TA. Intersubunit signal transmission in integrins by a receptor-like interaction with a pull spring. Proc Natl Acad Sci U S A 2004; 101:2906-11. PubMed
  • Yang W, Shimaoka M, Chen J, Springer TA. Activation of integrin beta-subunit I-like domains by one-turn C-terminal alpha-helix deletions. Proc Natl Acad Sci U S A 2004; 101:2333-8. PubMed
  • Yang W, Shimaoka M, Chen J, Springer TA. Activation of integrin {beta}-subunit I-like domains by one-turn C-terminal {alpha}-helix deletions. Proc Natl Acad Sci U S A 2004. PubMed
  • Beglova N, Blacklow SC, Takagi J, Springer TA. Cysteine-rich module structure reveals a fulcrum for integrin rearrangement upon activation. Nat Struct Biol 2002; 9:282-7. PubMed
  • Ma Q, Shimaoka M, Lu C, Jing H, Carman CV, Springer TA. Activation-induced conformational changes in the I domain region of lymphocyte function-associated antigen 1. J Biol Chem 2002; 277:10638-41. PubMed
  • Jeon H, Meng W, Takagi J, Eck MJ, Springer TA, Blacklow SC. Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. Nat Struct Biol 2001; 8:499-504. PubMed
  • Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 1999; 10:463-71. PubMed
  • Casasnovas JM, Pieroni C, Springer TA. Lymphocyte function-associated antigen-1 binding residues in intercellular adhesion molecule-2 (ICAM-2) and the integrin binding surface in the ICAM subfamily. Proc Natl Acad Sci U S A 1999; 96:3017-22. PubMed
  • Oxvig C, Lu C, Springer TA. Conformational changes in tertiary structure near the ligand binding site of an integrin I domain. Proc Natl Acad Sci U S A 1999; 96:2215-20. PubMed
  • Chen S, Springer TA. An automatic braking system that stabilizes leukocyte rolling by an increase in selectin bond number with shear. J Cell Biol 1999; 144:185-200. PubMed
  • Springer TA. An extracellular beta-propeller module predicted in lipoprotein and scavenger receptors, tyrosine kinases, epidermal growth factor precursor, and extracellular matrix components. J Mol Biol 1998; 283:837-62. PubMed
  • Alon R, Chen S, Fuhlbrigge R, Puri KD, Springer TA. The kinetics and shear threshold of transient and rolling interactions of L-selectin with its ligand on leukocytes. Proc Natl Acad Sci U S A 1998; 95:11631-6. PubMed
  • Ma Q, Jones D, Borghesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A 1998; 95:9448-53. PubMed
  • Kitayama J, Mackay CR, Ponath PD, Springer TA. The C-C chemokine receptor CCR3 participates in stimulation of eosinophil arrest on inflammatory endothelium in shear flow. J Clin Invest 1998; 101:2017-24. PubMed
  • Puri KD, Chen S, Springer TA. Modifying the mechanical property and shear threshold of L-selectin adhesion independently of equilibrium properties. Nature 1998; 392:930-3. PubMed
  • Casasnovas JM, Stehle T, Liu JH, Wang JH, Springer TA. A dimeric crystal structure for the N-terminal two domains of intercellular adhesion molecule-1. Proc Natl Acad Sci U S A 1998; 95:4134-9. PubMed
  • Bleul CC, Schultze JL, Springer TA. B lymphocyte chemotaxis regulated in association with microanatomic localization, differentiation state, and B cell receptor engagement. J Exp Med 1998; 187:753-62. PubMed
  • Clark RA, Fuhlbrigge RC, Springer TA. L-Selectin ligands that are O-glycoprotease resistant and distinct from MECA-79 antigen are sufficient for tethering and rolling of lymphocytes on human high endothelial venules. J Cell Biol 1998; 140:721-31. PubMed
  • Parolin C, Borsetti A, Choe H, Farzan M, Kolchinsky P, Heesen M, Ma Q, Gerard C, Pal. Use of murine CXCR-4 as a second receptor by some T-cell-tropic human immunodeficiency viruses. J Virol 1998; 72:1652-6. PubMed
  • Casasnovas JM, Springer TA, Liu JH, Harrison SC, Wang JH. Crystal structure of ICAM-2 reveals a distinctive integrin recognition surface. Nature 1997; 387:312-5. PubMed
  • Chen S, Alon R, Fuhlbrigge RC, Springer TA. Rolling and transient tethering of leukocytes on antibodies reveal specializations of selectins. Proc Natl Acad Sci U S A 1997; 94:3172-7. PubMed
  • Bleul CC, Wu L, Hoxie JA, Springer TA, Mackay CR. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lymphocytes. Proc Natl Acad Sci U S A 1997; 94:1925-30. PubMed
  • Kitayama J, Carr MW, Roth SJ, Buccola J, Springer TA. Contrasting responses to multiple chemotactic stimuli in transendothelial migration: heterologous desensitization in neutrophils and augmentation of migration in eosinophils. J Immunol 1997; 158:2340-9. PubMed
  • Springer TA. Folding of the N-terminal, ligand-binding region of integrin alpha-subunits into a beta-propeller domain. Proc Natl Acad Sci U S A 1997; 94:65-72. PubMed
  • Alon R, Fuhlbrigge RC, Finger EB, Springer TA. Interactions through L-selectin between leukocytes and adherent leukocytes nucleate rolling adhesions on selectins and VCAM-1 in shear flow. J Cell Biol 1996; 135:849-65. PubMed
  • Fuhlbrigge RC, Alon R, Puri KD, Lowe JB, Springer TA. Sialylated, fucosylated ligands for L-selectin expressed on leukocytes mediate tethering and rolling adhesions in physiologic flow conditions. J Cell Biol 1996; 135:837-48. PubMed
  • Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1) J Exp Med 1996; 184:1101-9. PubMed
  • Diacovo TG, Puri KD, Warnock RA, Springer TA, von Andrian UH. Platelet-mediated lymphocyte delivery to high endothelial venules. Science 1996; 273:252-5. PubMed
  • Carr MW, Alon R, Springer TA. The C-C chemokine MCP-1 differentially modulates the avidity of beta 1 and beta 2 integrins on T lymphocytes. Immunity 1996; 4:179-87. PubMed
  • Finger EB, Puri KD, Alon R, Lawrence MB, von Andrian UH, Springer TA. Adhesion through L-selectin requires a threshold hydrodynamic shear. Nature 1996; 379:266-9. PubMed
  • Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, Springer TA. The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol 1995; 128:1243-53. PubMed
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