Four crystal structures of human LLT1, a ligand of human NKR-P1, in varied glycosylation and oligomerization states

Skálová, Tereza; Bláha, J.; Harlos, K.; Dušková, Jarmila; Kovaĺ, T.; Stránský, Jan; Hašek, Jindřich; Vaněk, Ondřej; Dohnálek, Jan

doi:10.1107/s1399004714027928

Cited by 23 publications

(25 citation statements)

References 64 publications

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“…1 ). In contrast, Clr-b was most similar to the closely related family member Clr-g 31 , and also displayed considerable structural homology to the human NKR-P1A ligand LLT-1 32 ( Z -score ≈ 22.8, r.m.s.d ≈ 1.0 Å over 117 aligned Cα residues). Notably, NKR-P1B and Clr-b were highly structurally similar to each other (r.m.s.d 1.6 Å over 87 aligned Cα atoms), with the main distinction being a reorientation of the α2-helix of NKR-P1B by ~10° (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Recognition of host Clr-b by the inhibitory NKR-P1B receptor provides a basis for missing-self recognition

et al. 2018

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The interaction between natural killer (NK) cell inhibitory receptors and their cognate ligands constitutes a key mechanism by which healthy tissues are protected from NK cell-mediated lysis. However, self-ligand recognition remains poorly understood within the prototypical NKR-P1 receptor family. Here we report the structure of the inhibitory NKR-P1B receptor bound to its cognate host ligand, Clr-b. NKR-P1B and Clr-b interact via a head-to-head docking mode through an interface that includes a large array of polar interactions. NKR-P1B:Clr-b recognition is extremely sensitive to mutations at the heterodimeric interface, with most mutations severely impacting both Clr-b binding and NKR-P1B receptor function to implicate a low affinity interaction. Within the structure, two NKR-P1B:Clr-b complexes are cross-linked by a non-classic NKR-P1B homodimer, and the disruption of homodimer formation abrogates Clr-b recognition. These data provide an insight into a fundamental missing-self recognition system and suggest an avidity-based mechanism underpins NKR-P1B receptor function.

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Section: Resultsmentioning

confidence: 99%

Recognition of host Clr-b by the inhibitory NKR-P1B receptor provides a basis for missing-self recognition

et al. 2018

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“…1J). Altogether, these data demonstrate that AICL homodimers are linked in a homodimer based on the structure of LLT1 (Protein Data Bank code: 4QKH) (69). Structure of the homodimeric AICL CTLD, including positioning of Cys 87 , was modeled using Swiss Model software and Swiss Protein Data Bank Viewer 4.1.0 (http://www.expasy.org/spdbv/) (70) with a-helices in red and b-sheets in green, and zoomed into the position of cysteine 87 below.…”

Section: Resultsmentioning

confidence: 73%

Cellular Mechanisms Controlling Surfacing of AICL Glycoproteins, Cognate Ligands of the Activating NK Receptor NKp80

Neuss

Bartel

Born

et al. 2018

The Journal of Immunology

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AICL glycoproteins are cognate activation-induced ligands of the C-type lectin-like receptor NKp80, which is expressed on virtually all mature human NK cells, and NKp80-AICL interaction stimulates NK cell effector functions such as cytotoxicity and cytokine secretion. Notably, AICL and NKp80 are encoded by adjacent genes in the NK gene complex and are coexpressed by human NK cells. Whereas AICL is intracellularly retained in resting NK cells, exposure of NK cells to proinflammatory cytokines results in AICL surfacing and susceptibility to NKp80-mediated NK fratricide. In this study, we characterize molecular determinants of AICL glycoproteins that cause intracellular retention, thereby controlling AICL surface expression. Cys residing within the C-type lectin-like domain not only ensures stable homodimerization of AICL glycoproteins by disulfide bonding, but Cys is also required for efficient cell surface expression of AICL homodimers and essential for AICL-NKp80 interaction. In contrast, cytoplasmic lysines act as negative regulators targeting AICL for proteasomal degradation. One atypical and three conventional -linked glycosylation sites in the AICL C-type lectin-like domain critically impact maturation and surfacing of AICL, which is strictly dependent on glycosylation of at least one conventional glycosylation site. However, although the extent of conventional-linked glycosylation positively correlates with AICL surface expression, the atypical glycosylation site impairs AICL surfacing. Stringent control of AICL surface expression by glycosylation is reflected by the pronounced interaction of AICL with calnexin and the impaired AICL expression in calnexin-deficient cells. Collectively, our data demonstrate that AICL expression and surfacing are tightly controlled by several independent cellular posttranslational mechanisms.

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“…These primary crystals already provided protein diffraction up to resolution of 3.2 Å and were later optimized leading to solution of LLT1 crystal structure [29].…”

Section: Llt1 Forms Non-covalent Dimer In Solution Independently Of Imentioning

confidence: 99%

Expression and purification of soluble and stable ectodomain of natural killer cell receptor LLT1 through high-density transfection of suspension adapted HEK293S GnTI− cells

Bláha

Pachl

Novák

et al. 2015

Protein Expression and Purification

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Four crystal structures of human LLT1, a ligand of human NKR-P1, in varied glycosylation and oligomerization states

Abstract: Four crystal structures of human LLT1, a ligand of human NKR-P1, are reported.

Cited by 23 publications

References 64 publications

Recognition of host Clr-b by the inhibitory NKR-P1B receptor provides a basis for missing-self recognition

Recognition of host Clr-b by the inhibitory NKR-P1B receptor provides a basis for missing-self recognition

Cellular Mechanisms Controlling Surfacing of AICL Glycoproteins, Cognate Ligands of the Activating NK Receptor NKp80

Expression and purification of soluble and stable ectodomain of natural killer cell receptor LLT1 through high-density transfection of suspension adapted HEK293S GnTI− cells

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