Recognition of the Thomsen-Friedenreich Pancarcinoma Carbohydrate Antigen by a Lamprey Variable Lymphocyte Receptor

Luo, Ming; Velikovsky, Carlos A.; Siddiqui, M. Arshad; Hong, Xue-Ren; Barchi, Joseph J.; Gildersleeve, Jeffrey C.; Pancer, Zeev; Mariuzza, Roy A.

doi:10.1074/jbc.m113.480467

Cited by 37 publications

(61 citation statements)

References 36 publications

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“…Similar carbohydrate recognition through tryptophan residues was seen by Luo et al in recognition of Thomsen-Friedenreich antigen by a VLR protein. 18 Although our observed affinities are an order of magnitude lower than reported for the full-length NOD2 protein 55 it is important to note that CLRR2 is representative of the entire NOD family and shares only 70% sequence identity with NOD2.…”

Section: Chemical Denaturationmentioning

confidence: 53%

“…43 The sequence identities for the NOD and NLRP-b consensus sequences are 57%; however, the overall conservation in most positions in the NLRP-b sequence exceeds the NOD. For example, positions 6,13,18,19,21,22,25,26, and 27 in the NLRP-b MSA all have significantly higher conservation than the NOD sequence [ Fig. 1(b)].…”

Section: Consensus Sequence Of Nod Subgroupmentioning

confidence: 99%

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Consensus design of a NOD receptor leucine rich repeat domain with binding affinity for a muramyl dipeptide, a bacterial cell wall fragment

2014

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Repeat proteins have recently emerged as especially well-suited alternative binding scaffolds due to their modular architecture and biophysical properties. Here we present the design of a scaffold based on the consensus sequence of the leucine rich repeat (LRR) domain of the NOD family of cytoplasmic innate immune system receptors. Consensus sequence design has emerged as a protein design tool to create de novo proteins that capture sequence-structure relationships and interactions present in nature. The multiple sequence alignment of 311 individual LRRs, which are the putative ligand-recognition domain in NOD proteins, resulted in a consensus sequence protein containing two internal and N-and C-capping repeats named CLRR2. CLRR2 protein is a stable, monomeric, and cysteine free scaffold that without any affinity maturation displays micromolar binding to muramyl dipeptide, a bacterial cell wall fragment. To our knowledge, this is the first report of direct interaction of a NOD LRR with a physiologically relevant ligand.

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Section: Chemical Denaturationmentioning

confidence: 53%

Section: Consensus Sequence Of Nod Subgroupmentioning

confidence: 99%

Consensus design of a NOD receptor leucine rich repeat domain with binding affinity for a muramyl dipeptide, a bacterial cell wall fragment

2014

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“…3B). This insert, whose secondary structure also varies, is critical for recognition of protein and carbohydrate antigens (14,15,(22)(23)(24)(25). The average length of the LRRCT insert in VLRCs (2 residues) is much less than in VLRAs (10 residues) or VLRBs (8 residues), and sequence variation in the LRRCT module of VLRCs is substantially lower than in LRRCT of the other two VLR types (19,29).…”

Section: Resultsmentioning

confidence: 99%

Selection of the lamprey VLRC antigen receptor repertoire

Holland

Gao

Hirano

et al. 2014

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

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The alternative adaptive immune system of jawless vertebrates is based on different isotypes of variable lymphocyte receptors (VLRs) that are composed of leucine-rich repeats (LRRs) and expressed by distinct B-and T-like lymphocyte lineages. VLRB is expressed by B-like cells, whereas VLRA and VLRC are expressed by two T-like lineages that develop in the thymoid, a thymus-like structure in lamprey larvae. In each case, stepwise combinatorial insertions of different types of short donor LRR cassettes into incomplete germ-line genes are required to generate functional VLR gene assemblies. It is unknown, however, whether the diverse repertoires of VLRs that are expressed by peripheral blood lymphocytes are shaped by selection after their assembly. Here, we identify signatures of selection in the peripheral repertoire of VLRC antigen receptors that are clonally expressed by one of the T-like cell types in lampreys. Selection strongly favors VLRC molecules containing four internal variable leucine-rich repeat (LRRV) modules, although VLRC assemblies encoding five internal modules are initially equally frequent. In addition to the length selection, VLRC molecules in VLRC + peripheral lymphocytes exhibit a distinct pattern of high entropy sites in the N-terminal LRR1 module, which is inserted next to the germ-line-encoded LRRNT module. This is evident in comparisons to VLRC gene assemblies found in the thymoid and to VLRC gene assemblies found in some VLRA + cells. Our findings are the first indication to our knowledge that selection operates on a VLR repertoire and provide a framework to establish the mechanism by which this selection occurs during development of the VLRC + lymphocyte lineage.adaptive immunity | molecular evolution | agnathans

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“…Several carbohydrate-binding lectins and mammalian antibodies have been investigated for specific binding to glycosylated proteins; however, these binders generally suffer from low affinity and broad specificity, thus limiting their clinical utility [39][40][41][42]. Variable lymphocyte receptors (VLRs), which are LRRs involved in the adaptive immunity of jawless vertebrates, have been successfully engineered for recognition of several glycosylated proteins [12,43,44]. For example, Hong et al [33] describe a yeast surface display screen of VLRs from lamprey that enabled the selection of binders for a number of glycan targets with nanomolar affinities.…”

Section: Other Biomolecular Targetsmentioning

confidence: 99%

“…Designed ankyrin repeat proteins (DARPins), tetratricopeptide repeats (TPRs), armadillo repeat proteins (ARMs) and leucine rich repeat proteins (LRRs) have all been used for development of high-affinity binders [9][10][11][12][13]. For this reason, designed repeat proteins that have been successfully used for imaging and/or biosensing applications will remain the focus of this review.…”

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confidence: 99%

Designing repeat proteins for biosensors and medical imaging

Parker

Grove

2015

Biochemical Society Transactions

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Advances in protein engineering tools, both computational and experimental, has afforded many new protein structures and functions. Here, we present a snapshot of repeat-protein engineering efforts towards new, versatile, alternative binding scaffolds for use in analytical sensors and as imaging agents. Analytical assays, sensors and imaging agents based on the direct binding of analyte are increasingly important for research and diagnostics in medicine, food safety, and national security.

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Recognition of the Thomsen-Friedenreich Pancarcinoma Carbohydrate Antigen by a Lamprey Variable Lymphocyte Receptor

Cited by 37 publications

References 36 publications

Consensus design of a NOD receptor leucine rich repeat domain with binding affinity for a muramyl dipeptide, a bacterial cell wall fragment

Consensus design of a NOD receptor leucine rich repeat domain with binding affinity for a muramyl dipeptide, a bacterial cell wall fragment

Selection of the lamprey VLRC antigen receptor repertoire

Designing repeat proteins for biosensors and medical imaging

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