Structure-Based Engineering for PTPσ-Targeted Therapeutic Development.
- 1Department of Bioengineering, College of Engineering, Hanyang University, Seoul 04673, Republic of Korea.
Abstract
Protein tyrosine phosphatase sigma (PTPσ) is a member of the leukocyte common antigen-related (LAR) family of receptor-type protein tyrosine phosphatases. Its architecture integrates an extracellular proteoglycan-sensing region, a single-pass transmembrane helix, and tandem intracellular phosphatase domains. In neural injury, inhibition of PTPσ signaling can relieve chondroitin sulfate proteoglycan (CSPG)-mediated restriction of axonal growth and plasticity. In rheumatoid arthritis (RA), by contrast, restoration of PTPσ activity in fibroblast-like synoviocytes can suppress pathogenic migration and invasion. Structural studies have established a proteoglycan-switch model in which glycosaminoglycan engagement of the N-terminal immunoglobulin-like domains and extracellular clustering regulate intracellular phosphatase activity. Recent work demonstrated that antibodies to the membrane-proximal fibronectin type III-like domain 9 (Fn9) can regulate PTPσ oligomerization and syndecan-4 association in rheumatoid arthritis. Structure-guided protein engineering has converted a poorly soluble PTPσ Ig1-Ig2 decoy into developable Fc-fusion variants with substantially improved solubility and expression yield while retaining glycosaminoglycan binding and cell-based activity. This review summarizes the structural basis of PTPσ regulation and evaluates therapeutic modalities and engineering strategies for advancing PTPσ-directed biologics toward clinical candidates.
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BibTeX
@article{kim2026structurebased,
title = {{Structure-Based Engineering for PTPσ-Targeted Therapeutic Development.}},
author = {Hyunjin Kim and Seong Eon Ryu},
journal = {International journal of molecular sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27198659},
url = {https://europepmc.org/article/MED/42883905},
note = {CC BY},
}
RIS
TY - JOUR
TI - Structure-Based Engineering for PTPσ-Targeted Therapeutic Development.
AU - Hyunjin Kim
AU - Seong Eon Ryu
PY - 2026
DA - 2026/09/28
JO - International journal of molecular sciences
DO - 10.3390/ijms27198659
UR - https://europepmc.org/article/MED/42883905
AB - Protein tyrosine phosphatase sigma (PTPσ) is a member of the leukocyte common antigen-related (LAR) family of receptor-type protein tyrosine phosphatases. Its architecture integrates an extracellular proteoglycan-sensing region, a single-pass transmembrane helix, and tandem intracellular phosphatase domains. In neural injury, inhibition of PTPσ signaling can relieve chondroitin sulfate proteoglycan (CSPG)-mediated restriction of axonal growth and plasticity. In rheumatoid arthritis (RA), by contrast, restoration of PTPσ activity in fibroblast-like synoviocytes can suppress pathogenic migration and invasion. Structural studies have established a proteoglycan-switch model in which glycosaminoglycan engagement of the N-terminal immunoglobulin-like domains and extracellular clustering regulate intracellular phosphatase activity. Recent work demonstrated that antibodies to the membrane-proximal fibronectin type III-like domain 9 (Fn9) can regulate PTPσ oligomerization and syndecan-4 association in rheumatoid arthritis. Structure-guided protein engineering has converted a poorly soluble PTPσ Ig1-Ig2 decoy into developable Fc-fusion variants with substantially improved solubility and expression yield while retaining glycosaminoglycan binding and cell-based activity. This review summarizes the structural basis of PTPσ regulation and evaluates therapeutic modalities and engineering strategies for advancing PTPσ-directed biologics toward clinical candidates.
SN - 1422-0067
ER -