Photo of Timothy A. Springer,  PhD

Timothy A. Springer, PhD

Boston Children's Hospital

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

Timothy A. Springer, PhD

Boston Children's Hospital


  • 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


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 from Harvard Catalyst Profiles

Powered by Harvard Catalyst
  • Renella R, Gagne K, Beauchamp E, Fogel J, Perlov A, Sola M, Schlaeger T, Hofmann I, Shimamura A, Ebert BL, Schmitz-Abe K, Markianos K, Murphy K, Sun L, Rockowitz S, Sliz P, Campagna DR, Springer TA, Bahl C, Agarwal S, Fleming MD, Williams DA. Congenital X-linked neutropenia with myelodysplasia and somatic tetraploidy due to a germline mutation in SEPT6. Am J Hematol 2021. PubMed
  • Jensen RK, Bajic G, Sen M, Springer TA, Vorup-Jensen T, Andersen GR. Complement Receptor 3 Forms a Compact High-Affinity Complex with iC3b. J Immunol 2021. PubMed
  • Hou L, Voit RA, Sankaran VG, Springer TA, Yuki K. CD11c regulates hematopoietic stem and progenitor cells under stress. Blood Adv 2020; 4:6086-6097. PubMed
  • Wang J, Su Y, Iacob RE, Engen JR, Springer TA. General structural features that regulate integrin affinity revealed by atypical αVβ8. Nat Commun 2019; 10:5481. PubMed
  • Buß M, Tegtmeyer N, Schnieder J, Dong X, Li J, Springer TA, Backert S, Niemann HH. Specific high affinity interaction of Helicobacter pylori CagL with integrin α β promotes type IV secretion of CagA into human cells. FEBS J 2019. PubMed
  • Dong X, Leksa NC, Chhabra ES, Arndt JW, Lu Q, Knockenhauer KE, Peters RT, Springer TA. The von Willebrand factor D'D3 assembly and structural principles for factor VIII binding and concatemer biogenesis. Blood 2019; 133:1523-1533. PubMed
  • Feng J, Dong X, Pinello J, Zhang J, Lu C, Iacob RE, Engen JR, Snell WJ, Springer TA. Fusion surface structure, function, and dynamics of gamete fusogen HAP2. Elife 2018. PubMed
  • Qin Y, Garrison BS, Ma W, Wang R, Jiang A, Li J, Mistry M, Bronson RT, Santoro D, Franco C, Robinton DA, Stevens B, Rossi DJ, Lu C, Springer TA. A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System. Cell 2018; 174:156-171.e16. PubMed
  • Sen M, Koksal AC, Yuki K, Wang J, Springer TA. Ligand and cation-induced structural alterations of the leukocyte integrin LFA-1. J Biol Chem 2018. PubMed
  • Dong X, Zhao B, Lin FY, Lu C, Rogers BN, Springer TA. High integrin αβaffinity reached by hybrid domain deletion slows ligand-binding on-rate. Proc Natl Acad Sci U S A 2018; 115:E1429-E1436. PubMed
  • Moore TI, Aaron J, Chew TL, Springer TA. Measuring Integrin Conformational Change on the Cell Surface with Super-Resolution Microscopy. Cell Rep 2018; 22:1903-1912. PubMed
  • Le VQ, Iacob RE, Tian Y, McConaughy W, Jackson J, Su Y, Zhao B, Engen JR, Pirruccello-Straub M, Springer TA. Tolloid cleavage activates latent GDF8 by priming the pro-complex for dissociation. EMBO J 2018; 37:384-397. PubMed
  • Li J, Springer TA. Energy landscape differences among integrins establish the framework for understanding activation. J Cell Biol 2018; 217:397-412. PubMed
  • Nordenfelt P, Moore TI, Mehta SB, Kalappurakkal JM, Swaminathan V, Koga N, Lambert TJ, Baker D, Waters JC, Oldenbourg R, Tani T, Mayor S, Waterman CM, Springer TA. Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration. Nat Commun 2017; 8:2047. PubMed
  • Zhao B, Xu S, Dong X, Lu C, Springer TA. Prodomain-Growth Factor Swapping in the Structure of pro-TGF-β1. J Biol Chem 2017. PubMed
  • Swaminathan V, Kalappurakkal JM, Mehta SB, Nordenfelt P, Moore TI, Koga N, Baker DA, Oldenbourg R, Tani T, Mayor S, Springer TA, Waterman CM. Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions. Proc Natl Acad Sci U S A 2017; 114:10648-10653. PubMed
  • Wang J, Dong X, Zhao B, Li J, Lu C, Springer TA. Atypical interactions of integrin αVβ8 with pro-TGF-β1. Proc Natl Acad Sci U S A 2017; 114:E4168-E4174. PubMed
  • Li J, Springer TA. Integrin extension enables ultrasensitive regulation by cytoskeletal force. Proc Natl Acad Sci U S A 2017; 114:4685-4690. PubMed
  • Dong X, Zhao B, Iacob RE, Zhu J, Koksal AC, Lu C, Engen JR, Springer TA. Force interacts with macromolecular structure in activation of TGF-β. Nature 2017; 542:55-59. PubMed
  • Gansner JM, Leung AD, Superdock M, Blair MC, Ammerman MB, Durand EM, Barut B, Handin RI, Stachura DL, Lu C, Springer TA, Zon LI. Sorting zebrafish thrombocyte lineage cells with a Cd41 monoclonal antibody enriches hematopoietic stem cell activity. Blood 2017. PubMed
  • Li J, Su Y, Xia W, Qin Y, Humphries MJ, Vestweber D, Cabañas C, Lu C, Springer TA. Conformational equilibria and intrinsic affinities define integrin activation. EMBO J 2017. PubMed
  • Nordenfelt P, Elliott HL, Springer TA. Coordinated integrin activation by actin-dependent force during T-cell migration. Nat Commun 2016; 7:13119. PubMed
  • Hinck AP, Mueller TD, Springer TA. Structural Biology and Evolution of the TGF-β Family. Cold Spring Harb Perspect Biol 2016. PubMed
  • Su Y, Xia W, Li J, Walz T, Humphries MJ, Vestweber D, Cabañas C, Lu C, Springer TA. Relating conformation to function in integrin α5β1. Proc Natl Acad Sci U S A 2016; 113:E3872-81. PubMed
  • Swearingen KE, Lindner SE, Shi L, Shears MJ, Harupa A, Hopp CS, Vaughan AM, Springer TA, Moritz RL, Kappe SH, Sinnis P. Interrogating the Plasmodium Sporozoite Surface: Identification of Surface-Exposed Proteins and Demonstration of Glycosylation on CSP and TRAP by Mass Spectrometry-Based Proteomics. PLoS Pathog. 2016; 12:e1005606. PubMed
  • Sen M, Springer TA. Leukocyte integrin αLβ2 headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops. Proc Natl Acad Sci U S A 2016; 113:2940-5. PubMed
  • Lin FY, Zhu J, Eng ET, Hudson NE, Springer TA. β-subunit Binding is Sufficient for Ligands to open the Integrin αIIbβ3 Headpiece. J Biol Chem 2015. PubMed
  • Zhu J, Zhu J, Bougie DW, Aster RH, Springer TA. Structural basis for quinine-dependent antibody binding to platelet integrin αIIbβ3. Blood 2015. PubMed
  • Bury L, Falcinelli E, Chiasserini D, Springer TA, Italiano JE, Gresele P. Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in Glanzmann variants. Haematologica 2015. PubMed
  • 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
  • Xia W, Springer TA. Metal ion and ligand binding of integrin α5β1. Proc Natl Acad Sci U S A 2014; 111:17863-8. PubMed
  • Dong X, Hudson NE, Lu C, Springer TA. Structural determinants of integrin β-subunit specificity for latent TGF-β. Nat Struct Mol Biol 2014; 21:1091-6. 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, αXβ2. J Cell Biol 2013; 203:629-42. PubMed
  • Yu Y, Schürpf T, Springer TA. How natalizumab binds and antagonizes α4 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. α(V)β(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 2010; 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