The variable lymphocyte receptor as an antibody alternative

Waters, Elizabeth A; Shusta, Eric V.

doi:10.1016/j.copbio.2018.02.016

Cited by 10 publications

(8 citation statements)

References 45 publications

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“…Based on repeat protein domains, these proteins are simple to design and modular, with highly variable binding surfaces. Compared with immunoglobulins, these proteins offer high affinity and specificity for their targets . While many protein engineering efforts are only able to target proteins and peptides, these engineered immune proteins are able to target glycans as well, filling an important gap in tools for research and biomedical applications.…”

Section: Discussionmentioning

confidence: 99%

“…Lampreys and hagfish, the surviving jawless vertebrates, have adaptive immune system proteins that share characteristics of the adaptive and innate immune systems in jawed vertebrates, as they are highly variable and specific, but use LRR domains as recognition elements . Three distinct types of VLR (A, B, and C) have been identified, with VLRB proteins most commonly used in VLR applications as they are expressed solubly . Alder et al .…”

Section: Non‐immunoglobulin Immune System Proteinsmentioning

confidence: 99%

“…VLRs are rapidly becoming a useful antibody alternative, and were recently the subject of an excellent comprehensive review by Waters and Shusta . They are able to bind to both proteins and glycans with high specificity and affinity.…”

Section: Non‐immunoglobulin Immune System Proteinsmentioning

confidence: 99%

“…The cDNA from this immunization can be harvested, and better binding engineered through directed evolution . Though often expressed without LRRCT to create monomeric VLRs, expressing such protein as a multimer can increase the avidity by a factor of nearly 1000 …”

Section: Engineered Binding Scaffoldsmentioning

confidence: 99%

“…In the search for better recognition agents, many different scaffolds have emerged; some notable examples are peptide and DNA aptamers, affimers, and anticalins, among others. The motivation and results of this research have been extensively reviewed in recent years . among these scaffolds, repeat proteins such as designed ankyrin repeat proteins (DARPins) tetratricopeptide repeat proteins (TPRs), and armadillo repeats have emerged as a promising class of scaffolds.…”

Section: Introductionmentioning

confidence: 99%

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Engineering repeat proteins of the immune system

McCord

Grove

2020

Biopolymers

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Limitations associated with immunoglobulins have motivated the search for novel binding scaffolds. Repeat proteins have emerged as one promising class of scaffolds, but often are limited to binding protein and peptide targets. An exception is the repeat proteins of the immune system, which have in recent years served as an inspiration for binding scaffolds which can bind glycans and other classes of biomolecule.Like other repeat proteins, these proteins can be very stable and have a monomeric mode of binding, with elongated and highly variable binding surfaces. The ability to target glycans and glycoproteins fill an important gap in current tools for research and biomedical applications.

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Section: Discussionmentioning

confidence: 99%

Section: Non‐immunoglobulin Immune System Proteinsmentioning

confidence: 99%

Section: Non‐immunoglobulin Immune System Proteinsmentioning

confidence: 99%

Section: Engineered Binding Scaffoldsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Engineering repeat proteins of the immune system

McCord

Grove

2020

Biopolymers

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The High‐Resolution Structure of a Variable Lymphocyte Receptor From Petromyzon marinus Capable of Binding to the Brain Extracellular Matrix

Appelt,

Thoden,

Gehrke

et al. 2024

Proteins

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Variable lymphocyte receptors (VLRs) are antigen receptors derived from the adaptive immune system of jawless vertebrates such as lamprey (Petromyzon marinus). First discovered in 2004, VLRs have been the subject of numerous biochemical and structural investigations. Due to their unique antigen binding properties, VLRs have been leveraged as possible drug delivery agents. One such VLR, previously identified and referred to as P1C10, was shown to bind to the brain extracellular matrix. Here, we present the high‐resolution X‐ray crystal structure of this VLR determined to 1.3 Å resolution. The fold is dominated by a six‐stranded mixed β‐sheet which provides a concave surface for possible antigen binding. Electron density corresponding to a 4‐(2‐hydroxyethyl)piperazine‐1‐propanesulfonic acid buffer molecule (HEPPS) was found in this region. By comparing the P1C10 molecular architecture and its buffer binding residues with those of other VLRs previously reported, it was possible to illustrate how this unique class of proteins can accommodate diverse binding partners. Additionally, we provide an analysis of the experimentally determined structure compared to the models generated by the commonly used AlphaFold and iTASSER structure prediction software packages.

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