Identification of a PAI‐1‐binding site within an intrinsically disordered region of vitronectin

Chu, Yuzhuo; Bucci, Joel C.; Peterson, Cynthia B.

doi:10.1002/pro.3770

Cited by 7 publications

(12 citation statements)

References 97 publications

(157 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The I (0) values calculated from the amino acid sequences of the 60% deuterated PAI-1 and VN in 0%, 20%, and 85% D 2 O, assuming a 1:1 complex at a concentration of 7.7 mg/mL, agreed with those obtained from the measured SANS data (Figure S2 and Table S1), indicating that the complex is 1:1 at these contrasts. This is supported by our recent study using stopped-flow kinetics to characterize biphasic binding of PAI-1 with SMB-IDD versus monophasic binding with SMB . The biphasic binding observed corroborates the binding of the IDD to PAI-1, with separate binding rates for the SMB and IDD regions; this prior work also demonstrated a 1:1 binding between these proteins …”

Section: Resultssupporting

confidence: 77%

“…This is supported by our recent study using stopped-flow kinetics to characterize biphasic binding of PAI-1 with SMB-IDD versus monophasic binding with SMB . The biphasic binding observed corroborates the binding of the IDD to PAI-1, with separate binding rates for the SMB and IDD regions; this prior work also demonstrated a 1:1 binding between these proteins …”

Section: Resultssupporting

confidence: 77%

“…This study employs sophisticated structural methods to determine the effect of PAI-1 binding on the structure of this linker region within VN. In a recent complementary investigation, we used truncated forms of vitronectin (SMB-IDD fragments) to pursue kinetic analyses that support this assignment for the secondary binding site . Our discoveries advance the field by providing structural information about an understudied domain of VN and generating models to understand how PAI-1 interactions in this region are key within the multistep pathway of assembly of PAI-1:vitronectin complexes that associate into higher-order forms and display altered cell binding and adhesion.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region

et al. 2019

Self Cite

View full text Add to dashboard Cite

Small-angle neutron scattering (SANS) measurements were pursued to study human vitronectin, a protein found in tissues and the circulation that regulates cell adhesion/ migration and proteolytic cascades that govern hemostasis and pericellular proteolysis. Many of these functions occur via interactions with its binding partner, plasminogen activator inhibitor-1 (PAI-1), the chief inhibitor of proteases that lyse and activate plasminogen. We focused on a region of vitronectin that remains uncharacterized from previous X-ray scattering, nuclear magnetic resonance, and computational modeling approaches and which we propose is involved in binding to PAI-1. This region, which bridges the N-terminal somatomedin B (SMB) domain with a large central β-propeller domain of vitronectin, appears unstructured and has characteristics of an intrinsically disordered domain (IDD). The effect of osmolytes was evaluated using circular dichroism and SANS to explore the potential of the IDD to undergo a disorder-to-order transition. The results suggest that the IDD favors a more ordered structure under osmotic pressure; SANS shows a smaller radius of gyration (R g ) and a more compact fold of the IDD upon addition of osmolytes. To test whether PAI-1 binding is also coupled to folding within the IDD structure, a set of SANS experiments with contrast variation were performed on the complex of PAI-1 with a vitronectin fragment corresponding to the N-terminal 130 amino acids (denoted the SMB-IDD because it contains the SMB domain and IDD in linear sequence). Analysis of the SANS data using the Ensemble Optimization Method confirms that the SMB-IDD adopts a more compact configuration when bound to PAI-1. Calculated structures for the PAI-1:SMB-IDD complex suggest that the IDD provides an interaction surface outside of the primary PAI-1-binding site located within the SMB domain; this binding is proposed to lead to the assembly of higher-order structures of vitronectin and PAI-1 commonly found in tissues.

show abstract

Section: Resultssupporting

confidence: 77%

Section: Resultssupporting

confidence: 77%

mentioning

confidence: 99%

See 1 more Smart Citation

Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…In plasma, PAI-1 is bound to the matrix protein vitronectin, which stabilizes PAI-1 in its active configuration and extends its half-life >10 times [ 85 ]. On the N-terminus of vitronectin exists a somatomedin B (SMB) domain of 44 amino acids that acts as a binding site for PAI-1 and uPAR; contiguous to it lies an RGD domain which is the binding site for integrins such as α v β 1 , α v β 3 , and α v β 5 [ 97 , 98 ]. PAI-1 interacts with a variety of molecules other than PAs such as vitronectin, heparin, and LRP to mediate cell migration [ 99 ].…”

Section: Plasminogen Activator–plasmin Systemmentioning

confidence: 99%

The Plasminogen–Activator Plasmin System in Physiological and Pathophysiological Angiogenesis

Ismail

Shaker

Bajou

2021

IJMS

View full text Add to dashboard Cite

Angiogenesis is a process associated with the migration and proliferation of endothelial cells (EC) to form new blood vessels. It is involved in various physiological and pathophysiological conditions and is controlled by a wide range of proangiogenic and antiangiogenic molecules. The plasminogen activator–plasmin system plays a major role in the extracellular matrix remodeling process necessary for angiogenesis. Urokinase/tissue-type plasminogen activators (uPA/tPA) convert plasminogen into the active enzyme plasmin, which in turn activates matrix metalloproteinases and degrades the extracellular matrix releasing growth factors and proangiogenic molecules such as the vascular endothelial growth factor (VEGF-A). The plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of uPA and tPA, thereby an inhibitor of pericellular proteolysis and intravascular fibrinolysis, respectively. Paradoxically, PAI-1, which is expressed by EC during angiogenesis, is elevated in several cancers and is found to promote angiogenesis by regulating plasmin-mediated proteolysis and by promoting cellular migration through vitronectin. The urokinase-type plasminogen activator receptor (uPAR) also induces EC cellular migration during angiogenesis via interacting with signaling partners. Understanding the molecular functions of the plasminogen activator plasmin system and targeting angiogenesis via blocking serine proteases or their interactions with other molecules is one of the major therapeutic strategies scientists have been attracted to in controlling tumor growth and other pathological conditions characterized by neovascularization.

show abstract

“…Self-regulation and signal propagation. PAI-1 is found bound to vitronectin, in a latent state which prevents its autolysis (100,101). The affinity of PAI-1 is lower to vitronectin than it is to uPA.…”

Section: Pasmentioning

confidence: 99%

Adipose‑PAS interactions in the context of its localised bio‑engineering potential (Review)

Nohawica

Errachid

Wyganowska‐Świątkowska

2021

Biomed Rep

View full text Add to dashboard Cite

Adipocytes are a known source of stem cells. They are easy to harvest, and are a suitable candidate for autogenous grafts. Adipose derived stem cells (ADSCs) have multiple target tissues which they can differentiate into, including bone and cartilage. In adipose tissue, ADSCs are able to differentiate, as well as providing energy and a supply of cytokines/hormones to manage the hypoxic and lipid/hormone saturated adipose environment. The plasminogen activation system (PAS) controls the majority of proteolytic activities in both adipose and wound healing environments, allowing for rapid cellular migration and tissue remodelling. While the primary activation pathway for PAS occurs through the urokinase plasminogen activator (uPA), which is highly expressed by endothelial cells, its function is not limited to enabling revascularisation. Proteolytic activity is dependent on protease activation, localisation, recycling mechanisms and substrate availability. uPA and uPA activated plasminogen allows pluripotent cells to arrive to new local environments and fulfil the niche demands. However, overstimulation, the acquisition of a migratory phenotype and constant protein turnover can be unconducive to the formation of structured hard and soft tissues. To maintain a suitable healing pattern, the proteolytic activity stimulated by uPA is modulated by plasminogen activator inhibitor 1. Depending on the physiological settings, different parts of the remodelling mechanism are activated with varying results. Utilising the differences within each microenvironment to recreate a desired niche is a valid therapeutic bio-engineering approach. By controlling the rate of protein turnover combined with a receptive stem cell lineage, such as ADSC, a novel avenue on the therapeutic opportunities may be identified, which can overcome limitations, such as scarcity of stem cells, low angiogenic potential or poor host tissue adaptation. Contents 1. Introduction 2. Adipocytes 3. PAS 4. Perspectives 5. Conclusions

show abstract

Identification of a PAI‐1‐binding site within an intrinsically disordered region of vitronectin

Cited by 7 publications

References 97 publications

Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region

Characterization of an Extensive Interface on Vitronectin for Binding to Plasminogen Activator Inhibitor-1: Adoption of Structure in an Intrinsically Disordered Region

The Plasminogen–Activator Plasmin System in Physiological and Pathophysiological Angiogenesis

Adipose‑PAS interactions in the context of its localised bio‑engineering potential (Review)

Contact Info

Product

Resources

About