NMR solution structure of the inserted domain of human leukocyte function associated antigen-1

Legge, Glen B.; Kriwacki, Richard W.; Chung, John Y. L.; Hommel, Ulrich; Ramage, Paul; Case, David A.; Dyson, H. Jane; Wright, Peter E.

doi:10.1006/jmbi.1999.3409

Cited by 75 publications

(94 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4B). The higher B factors of the C-terminal portion of the α7-helix seen here correlate well with reduced numbers of NMR distance restraints and higher rmsd among NMR ensembles (11) (Fig. 4B).…”

Section: Resultssupporting

confidence: 68%

“…β 2 integrin α subunits contain an inserted (αI) domain that binds to external ligands such as ICAMs. Crystal and NMR structures have revealed open/high-affinity and closed/low-affinity conformations of the LFA-1 αI domain, how it binds to ICAMs, and its dynamics, but only in isolation from other integrin domains (6)(7)(8)(9)(10)(11)(12). Here, we characterize crystal structures of the LFA-1 headpiece and rerefine previous α X β 2 ectodomain (13) and β 2 leg fragment (14, 15) crystal structures.…”

mentioning

confidence: 82%

See 1 more Smart Citation

Leukocyte integrin α _L β ₂ headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops

Şen

Springer

2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

High-resolution crystal structures of the headpiece of lymphocyte function-associated antigen-1 (integrin αLβ2) reveal how the αI domain interacts with its platform formed by the α-subunit β-propeller and β-subunit βI domains. The αLβ2 structures compared with αXβ2 structures show that the αI domain, tethered through its N-linker and a disulfide to a stable β-ribbon pillar near the center of the platform, can undergo remarkable pivoting and tilting motions that appear buffered by N-glycan decorations that differ between αL and αX subunits. Rerefined β2 integrin structures reveal details including pyroglutamic acid at the β2 N terminus and bending within the EGF1 domain. Allostery is relayed to the αI domain by an internal ligand that binds to a pocket at the interface between the β-propeller and βI domains. Marked differences between the αL and αX subunit β-propeller domains concentrate near the binding pocket and αI domain interfaces. Remarkably, movement in allostery in the βI domain of specificity determining loop 1 (SDL1) causes concerted movement of SDL2 and thereby tightens the binding pocket for the internal ligand.

show abstract

Section: Resultssupporting

confidence: 68%

mentioning

confidence: 82%

Leukocyte integrin α _L β ₂ headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops

Şen

Springer

2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…However, most of the peaks from other residues throughout the protein structure do not change, indicating that Mg 2ϩ binding does not induce a large scale conformational change of the ␣2-I domain in solution. This is similar to the results reported for LFA-1 (31).…”

Section: Association Of ␣2-i With Type I Collagen Peptide and Rkkhsupporting

confidence: 92%

Competitive Interactions of Collagen and a Jararhagin-derived Disintegrin Peptide with the Integrin α2-I Domain

Lambert

Bobkov

Smith

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Integrin ␣2␤1 is a major receptor required for activation and adhesion of platelets, through the specific recognition of collagen by the ␣2-I domain (␣2-I), which binds fibrillar collagen via Mg 2؉ -bridged interactions. The crystal structure of a truncated form of the ␣2-I domain, bound to a triple helical collagen peptide, revealed conformational changes suggestive of a mechanism where the ligand-bound I domain can initiate and propagate conformational change to the full integrin complex. Collagen binding by ␣2-I and fibrinogen-dependent platelet activity can be inhibited by snake venom polypeptides. Here we describe the inhibitory effect of a short cyclic peptide derived from the snake toxin metalloprotease jararhagin, with specific amino acid sequence RKKH, on the ability of ␣2-I to bind triple helical collagen. Isothermal titration calorimetry measurements showed that the interactions of ␣2-I with collagen or RKKH peptide have similar affinities, and NMR chemical shift mapping experiments with 15 N-labeled ␣2-I, and unlabeled RKKH peptide, indicate that the peptide competes for the collagen-binding site of ␣2-I but does not induce a large scale conformational rearrangement of the I domain.The integrins constitute a functionally versatile family of integral membrane receptors that mediate cell-cell and cellextracellular matrix interactions through their regulation of cell adhesion, differentiation, migration, and the immune response (1-5). Signal transduction is bi-directional through both outside-in and inside-out mechanisms. All integrins are heterodimers composed of subunits ␣ and ␤. Different combinations of subunits are expressed on different cell types with the interplay of 19 ␣ and 8 ␤ subunits, generating a family of 25 different heterodimers (3, 5).The integrin receptors share common structural features. The extracellular portions of the ␣ and ␤ subunits combine to form a globular "head" domain that is attached to a pair of membrane-spanning helical "stalks." Signal transduction is believed to involve an allosteric rearrangement characterized by the separation and reorientation of the stalk segments. The bidirectional nature of signal transduction is complex. Extracellular ligands induce outside-in signals by binding to fixed motifs in the head domain, whereas inside-out signaling ensues from intracellular interactions between relatively short structurally plastic control elements and a large repertoire of cellular proteins.In nine of the human ␣ subunits, ligand recognition is carried out by a 200-residue structurally conserved inserted (I) domain or a von Willebrand factor A domain (3, 5). The I and A domains adopt a Rossmann dinucleotide-binding fold, with a 6-stranded ␤-sheet surrounded by seven ␣-helices, and ligand recognition requires the binding of a single Mg 2ϩ ion to a metal ion-dependent adhesion (MIDAS) 2 motif (6, 7). The importance of the ␣ I domain for understanding conformational regulation and ligand binding for all integrins has been reviewed recently (5).Integrin ␣2␤1 is a member...

show abstract

“…In the locked-open ␣ L I domain, the double mutation K287C K294C was introduced. I domain was expressed in Escherichia coli BL21(DE3), purified, and refolded as described previously (19). For refolding of the locked-open I domain, 0.1 mM CuSO 4 and 0.1 mM o-phenanthroline were added to catalyze oxidative disulfide bond generation.…”

Section: Generation and Purification Of Soluble Proteinsmentioning

confidence: 99%

The Functional Interaction of the β2 Integrin Lymphocyte Function-Associated Antigen-1 with Junctional Adhesion Molecule-A Is Mediated by the I Domain

Fraemohs

Koenen

Ostermann

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

Binding of the β2 integrin LFA-1 (αLβ2) to junctional adhesion molecule-A (JAM-A) has been shown to enhance leukocyte adhesion and transendothelial migration. This is mediated by the membrane-proximal Ig-like domain 2 of JAM-A; however, the location of the JAM-A binding site in LFA-1 has not been identified. We have deleted the I domain in the αL subunit of LFA-1 and expressed this αL mutant in αl-deficient Jurkat J-β2.7 cells to demonstrate that the I domain of LFA-1 is crucial for their adhesion to immobilized JAM-A. This was substantiated by blocking the stimulated adhesion of wild-type Jurkat T cells or monocytic Mono Mac 6 cells to JAM-A using the I domain-directed mAb TS1/22 or the small molecule antagonist BIRT 377, which stabilizes the low-affinity conformation of the I domain. The immobilized LFA-1 I domain locked in the open high-affinity conformation was sufficient to support binding of transfected Chinese hamster ovary cells expressing JAM-A. Solid-phase binding assays confirmed a direct interaction of recombinant JAM-A with the immobilized locked-open I domain. These data provide the first evidence that the I domain of LFA-1 contains a functional binding site for JAM-A.

show abstract

NMR solution structure of the inserted domain of human leukocyte function associated antigen-1

Cited by 75 publications

References 46 publications

Leukocyte integrin α _L β ₂ headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops

Leukocyte integrin α _L β ₂ headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops

Competitive Interactions of Collagen and a Jararhagin-derived Disintegrin Peptide with the Integrin α2-I Domain

The Functional Interaction of the β2 Integrin Lymphocyte Function-Associated Antigen-1 with Junctional Adhesion Molecule-A Is Mediated by the I Domain

Contact Info

Product

Resources

About

NMR solution structure of the inserted domain of human leukocyte function associated antigen-1

Cited by 75 publications

References 46 publications

Leukocyte integrin α L β 2 headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops

Leukocyte integrin α L β 2 headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops

Competitive Interactions of Collagen and a Jararhagin-derived Disintegrin Peptide with the Integrin α2-I Domain

The Functional Interaction of the β2 Integrin Lymphocyte Function-Associated Antigen-1 with Junctional Adhesion Molecule-A Is Mediated by the I Domain

Contact Info

Product

Resources

About

Leukocyte integrin α _L β ₂ headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops

Leukocyte integrin α _L β ₂ headpiece structures: The αI domain, the pocket for the internal ligand, and concerted movements of its loops