Matthew Auton

Matthew Auton
Mayo Clinic - Rochester · Department of Hematology

Ph.D.

About

75
Publications
5,544
Reads
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2,087
Citations
Citations since 2017
25 Research Items
912 Citations
2017201820192020202120222023050100150
2017201820192020202120222023050100150
2017201820192020202120222023050100150
2017201820192020202120222023050100150
Introduction
My research involves the physical chemistry of solvation of amino acids and peptides, prediction of thermodynamic properties of protein folding and unfolding, the description of the complex thermodynamic behavior of multi-domain proteins, and the development of quantitatively predictive models for understanding the linkage between protein folding energetics and the conformational basis for protein function in health and disease.
Additional affiliations
January 2007 - December 2009
Rice University
January 2006 - December 2012
Baylor College of Medicine
January 2004 - December 2008
University of Texas Medical Branch at Galveston
Education
September 1998 - May 2004
University of Texas Medical Branch at Galveston
Field of study
  • Human Biological Chemistry and Genetics
August 1993 - August 1997
University of Texas at Arlington
Field of study
  • Biochemistry
August 1993 - August 1997
University of Texas at Arlington
Field of study
  • Chemistry

Publications

Publications (75)
Article
Full-text available
A redox autoinhibitory mechanism has previously been proposed in which the reduced state of the vicinal disulfide bond in the von Willebrand factor (VWF) A2 domain allows A2 to bind A1 and inhibit platelet adhesion to the A1-domain.1 The VWF A1A2A3 tri-domain was expressed with and without the vicinal disulfide in A2 (C1669S/C1670S) via atomic repl...
Article
Background : Injured patients have early changes to normal coagulation that can impact long term risk for thrombotic complications. There is little known about how age impacts biomarkers of coagulation after traumatic injury. In this pilot study, we aimed to characterize thrombin generation kinetics, a known predictor of venous thromboembolism, in...
Article
Background COVID-19-associated coagulopathy is incompletely understood. Objectives To characterize thrombin generation, Von Willebrand Factor (VWF), neutrophil extracellular traps (NETs), and their role in COVID-19 risk stratification in the emergency department (ED). Patients/methods Plasma samples from 67 ED COVID-19 patients were compared to 3...
Article
Full-text available
Gain-of-function (GoF) variants in GP1BA cause platelet-type von Willebrand disease (PT-VWD), a rare inherited autosomal dominant bleeding disorder characterized by enhanced platelet GPIbα-von Willebrand factor (VWF) interaction and thrombocytopenia. To date, only 6 variants causing PT-VWD have been described, 5 in the C-terminal disulfide loop of...
Article
Full-text available
Background Von Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF–platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction....
Article
Full-text available
The frequent overexpression of CD46 in malignant tumors has provided a basis to use vaccine-lineage measles virus (MeV) as an oncolytic virotherapy platform. However, widespread measles seropositivity limits the systemic deployment of oncolytic MeV for the treatment of metastatic neoplasia. Here, we report the development of MeV-Stealth, a modified...
Article
Background: Damage associated molecular patterns (DAMPs) stimulate endothelial syndecan-1 shedding and neutrophil extracellular traps (NET) formation. The role of NETs in trauma and trauma-induced hypercoagulability is unknown. We hypothesized that trauma patients with accelerated thrombin generation would have increased NETosis and syndecan-1 lev...
Article
Full-text available
The multimeric plasma glycoprotein von Willebrand factor (VWF) is best known for recruiting platelets to sites of injury during primary hemostasis. Generally, mutations in the VWF gene lead to loss of hemostatic activity and thus the bleeding disorder von Willebrand Disease. By employing cone and platelet aggregometry and microfluidic assays, we un...
Article
Full-text available
Introduction: We hypothesize that a patient (pt) with accelerated thrombin generation, time to peak height (ttPeak), will have a greater odds of meeting critical administration threshold (CAT) criteria (> 3 packed red blood cell [pRBC] transfusions [Tx] per 60 minute interval), within the first 24 hours after injury, independent of international n...
Article
Full-text available
Systemic inflammation can lead to coagulopathy and disseminated intravascular coagulation (DIC). In prior studies, the recombinant A2 domain of human von Willebrand factor (VWF; A2 protein) attenuated DIC and decreased mortality in lipopolysaccharide (LPS)-treated mice. Here, we performed studies to dissect the mechanism by which the A2 protein mod...
Article
Von Willebrand factor (VWF), an exceptionally large multimeric plasma glycoprotein, functions to initiate coagulation by agglutinating platelets in the blood stream to sites of vascular injury. This primary hemostatic function is perturbed in type 2 dysfunctional subtypes of von Willebrand disease (VWD) by mutations that alter the structure and fun...
Article
Full-text available
Background: A molecular basis for VWF self-inhibition has been proposed by which the N- and C-terminal flanking sequences of the globular A1 domain disulfide loop bind to and suppress the conformational dynamics of A1. These flanking sequences are rich in O-linked glycosylation (OLG) which is known to suppress platelet adhesion to VWF, presumably...
Article
Full-text available
BACKGROUND: Mutations in the β-switch of GPIbα cause gain-of-function in the platelet-type von Willebrand disease. Structures of free and A1 bound GPIbα suggest that the β-switch undergoes a conformational change from a coil to a β-hairpin. OBJECTIVES: Platelet-type VWD mutations have been proposed to stabilize the β-switch by shifting the equilib...
Article
In the absence of arabinose, the dimeric Escherichia coli regulatory protein of the L-arabinose operon, AraC, represses expression by looping the DNA between distant half-sites. Arabinose binding to the dimerization domains transition AraC to preferentially bind two adjacent DNA half-sites, which stimulates RNA polymerase transcription of the araBA...
Preprint
In the absence of arabinose, the dimeric Escherichia coli regulatory protein of the L-arabinose operon, AraC, represses expression by looping the DNA between distant half-sites, araO2 and araI1. Arabinose binding to the dimerization domains transition AraC to preferentially bind two adjacent DNA half-sites, araI1 and araI2, where it stimulates RNA...
Article
The frequent von Willebrand factor (VWF) variant p.Phe2561Tyr is located within the C4 domain, which also harbors the platelet GPIIb/IIIa-binding RGD sequence. To investigate its potential effect on hemostasis, we genotyped 865 patients with coronary artery disease (CAD), 915 with myocardial infarction (MI) and 417 controls (Ludwigshafen Risk and C...
Article
The frequent von Willebrand factor (VWF) variant p.Phe2561Tyr is located within the C4 domain, which also harbors the platelet GPIIb/IIIa-binding RGD sequence. To investigate its potential effect on hemostasis, we genotyped 865 patients with coronary artery disease (CAD), 915 with myocardial infarction (MI), and 417 control patients (Ludwigshafen R...
Article
Protein phase diagrams have a unique potential to identify the presence of additional thermodynamic states even when non-2-state character is not readily apparent from the experimental observables used to follow protein unfolding transitions. Two-state analysis of the von Willebrand factor A3 domain has previously revealed a discrepancy in the calo...
Poster
Full-text available
ABSTRACT: Background: Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor causes quantitative VWF deficiencies in the blood and von Willebrand disease. Two patients with C1272W and C1458Y mutations presented with DDAVP-induced severe thrombocytopenia that quickly relapsed to normal...
Article
Mutation of the cysteines forming the disulfide loop of the platelet GPIbα adhesive A1 domain of von Willebrand factor causes quantitative VWF deficiencies in the blood and von Willebrand disease. We report two cases of transient severe thrombocytopenia induced by DDAVP-treatment. Cys1272Trp and Cys1458Tyr mutations identified by genetic sequencing...
Article
Full-text available
Kleefstra syndrome (KS) (MIM# 610253), also known as 9q34 deletion syndrome, is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1). The clinical phenotype of KS includes moderate to severe intellectual disability with absent speech, hypotonia, brachycephaly, congenital heart defects, and d...
Article
Full-text available
Stabilizing the folded state of metastable and/or aggregation-prone proteins through exogenous ligand binding is an appealing strategy to decrease disease pathologies brought on by protein folding defects or deleterious kinetic transitions. Current methods of examining ligand binding to these marginally stable native states are limited because prot...
Article
Full-text available
von Willebrand factor׳s (VWF) primary hemostatic responsibility is to deposit platelets at sites of vascular injury to prevent bleeding. This function is mediated by the interaction between the VWF A1 domain and the constitutively active platelet receptor, GPIbα. The crystal structure of the A1 domain harboring the von Willebrand disease (vWD) type...
Article
Full-text available
Unusually large von Willebrand factor (ULVWF), the first responder to vascular injury in primary hemostasis, is designed to capture platelets under the high shear stress of rheological blood flow. In type 2M von Willebrand disease (VWD), two rare mutations (G1324A and G1324S) within the platelet GPIbα binding interface of the VWF A1 domain impair t...
Poster
Full-text available
We have performed a rigorous structure-function analysis of the von Willebrand factor A1 domain harboring two loss of function type 2M von Willebrand disease mutations. A crystal structure for G1324S is presented that is identical to that of the WT domain and to all other crystal structures including all type 2B gain of function mutations, indicati...
Article
Full-text available
Light chain (AL) amyloidosis is a fatal disease where monoclonal immunoglobulin light chains deposit as insoluble amyloid fibrils. For many years it has been considered that AL amyloid deposits are formed primarily by the variable domain, while its constant domain has been considered not to be amyloidogenic. However recent studies identify full len...
Article
The von Willebrand factor (VWF) A1 and A3 domains are structurally isomorphic yet exhibit distinct mechanisms of unfolding. The A1 domain, responsible for platelet adhesion to VWF in hemostasis, unfolds through a molten globule intermediate in an apparent three-state mechanism, while A3 unfolds by a classical two-state mechanism. Inspection of the...
Article
Background: Aortic stenosis-associated acquired von Willebrand syndrome (AS-AVWS) is caused by an accelerated degradation of the highest molecular weight von Willebrand factor (VWF) multimers (HMWM). We recently reported that the severity of the HMWM loss correlates with the severity of AS and patients’ bleeding tendency (Am J Cardiol, 2013;111:374...
Article
Von Willebrand disease (VWD) is the most common inherited human bleeding disorder. It is caused by deficiencies or defects in the plasma protein von Willebrand factor (vWF). The current classification of VWD consists of six distinct types. Type 1 and 3 result in a quantitative vWF deficiency in patients while the four type 2 variants (type 2A, 2B,...
Article
Molecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intri...
Article
The ionic liquid 1-ethyl-3-methyl imidazolium chloride (EMIM Cl) and the amino acid l-ArgHCl have been successfully used to improve the yield of oxidative refolding for various proteins. However, the molecular mechanisms behind the actions of such solvent additives - especially of ionic liquids - are still not well understood. In order to analyze t...
Article
The primary hemostatic von Willebrand factor (vWF) functions to sequester platelets from rheological blood flow and mediates their adhesion to damaged subendothelium at sites of vascular injury. We have surveyed the effect of 16 disease-causing mutations identified in patients diagnosed with the bleeding diathesis disorder, von Willebrand disease (...
Article
Clinical mutations in patients diagnosed with Type 2A von Willebrand disease (VWD) have been identified that break the single disulfide bond linking N- and C-termini in the vWF A1 domain. We have modeled the effect of these mutations on the disulfide-bonded structure of A1 by reducing and carboxy-amidating these cysteines. Solution biophysical stud...
Article
Unlabelled: The ionic liquid N-ethyl-N'-methyl imidazolium chloride (EMIMCl) has been described as being very efficient in promoting refolding of the recombinant plasminogen activator rPA. Our study reveals that molar concentrations of EMIMCl increase the solubility of native and unfolded proteins due to favorable interactions with amino acid side...
Article
We have analyzed the thermodynamic properties of the von Willebrand factor A3 domain using urea-induced unfolding at variable temperature and thermal unfolding at variable urea concentrations to generate a phase diagram that quantitatively describes the equilibrium between native and denatured states. From this analysis, we were able to determine c...
Article
Platelet attachment to von Willebrand factor (vWF) requires the interaction between the platelet GP1bα and exposed vWF-A1 domains. Structural insights into the mechanism of the A1-GP1bα interaction have been limited to an N-terminally truncated A1 domain that lacks residues Q1238 - E1260 that make up the linker between the D3 and A1 domains of VWF....
Poster
Full-text available
The thermodynamic properties of the von Willebrand factor A3 domain were analyzed using urea-induced unfolding at variable temperature and thermal unfolding at variable urea concentrations to generate a phase diagram that quantitatively describes the equilibrium between native and denatured states. From this analysis, we were able to determine cons...
Article
Reassembled high-density lipoproteins (rHDL) of various sizes and compositions containing apo A-I or apo A-II as their sole protein, dimyristoylphosphatidylcholine (DMPC), and various amounts of free cholesterol (FC) have been isolated and analyzed by differential scanning calorimetry (DSC) and by circular dichroism to determine their stability and...
Chapter
We discuss recent experiments and theories concerning protein col lapse and folding. Experiments using multicomponent solutions have revealed much about the mechanism of folding. Simulation and theory have been used to interpret thermodynamic and fluorescence correlation spectroscopy experi mental results. We consider the theoretical arguments usin...
Poster
Full-text available
The collagen-binding A3 domain of von Willebrand Factor (VWF) is responsible for the interaction of the blood factor with subendothelial tissue. However, while the biological function and the structure of the A3- domain is well understood, there is no detailed study of the thermodynamic properties of the protein which allows a future quantification...
Article
Background: Microsolubilization of dimyristoyl phosphatidylcholine (DMPC) by human apolipoprotein A-I is a frequently used model system for the identification of determinants of macrophage cholesterol efflux, the first step in reverse cholesterol transport (RCT) to hepatic disposal. Although many studies have focused on microsolubilization of DMPC,...
Article
Full-text available
von Willebrand factor (vWF) mediates platelet adhesion and thrombus formation via its interaction with the platelet receptor glycoprotein (GP)Ibα. We have analyzed two A1A2A3 tri-domain proteins to demonstrate that the amino acid sequence, Gln1238-Glu1260, in the N-terminal flanking region of the A1 domain, together with the association between the...
Article
Protein scientists have long used cosolutes to study protein stability. While denaturants, such as urea, have been employed for a long time, the attention became focused more recently on protein stabilizers, including osmolytes. Here, we provide practical experimental instructions for the use of both stabilizing and denaturing osmolytes with protei...
Article
In adaptation biology the discovery of intracellular osmolyte molecules that in some cases reach molar levels, raises questions of how they influence protein thermodynamics. We've addressed such questions using the premise that from atomic coordinates, the transfer free energy of a native protein (ΔG(tr,N)) can be predicted by summing measured wate...
Article
The binding of Von Willebrand Factor to platelets is dependent on the conformation of the A1 domain which binds to platelet GPIbalpha. This interaction initiates the adherence of platelets to the subendothelial vasculature under the high shear that occurs in pathological thrombosis. We have developed a thermodynamic strategy that defines the A1:GPI...
Article
Full-text available
This study used recombinant A1A2A3 tri-domain proteins to demonstrate that A domain association in von Willebrand factor (VWF) regulates the binding to platelet glycoprotein Ibalpha (GPIbalpha). We performed comparative studies between wild type (WT) A1 domain and the R1450E variant that dissociates the tri-domain complex by destabilizing the A1 do...
Article
In circulation, plasma glycoprotein von Willebrand Factor plays an important role in hemostasis and in pathological thrombosis under hydrodynamic forces. Mutations in the A1 domain of von Willebrand factor cause the hereditary types 2B and 2M von Willebrand disease that either enhance (2B) or inhibit (2M) the interaction of von Willebrand factor wi...
Article
Protein stability and solubility depend strongly on the presence of osmolytes, because of the protein preference to be solvated by either water or osmolyte. It has traditionally been assumed that only this relative preference can be measured, and that the individual solvation contributions of water and osmolyte are inaccessible. However, it is poss...
Article
Von Willebrand Factor (VWF) initiates platelet adhesion at sites of vessel injury via the binding of platelet glycoprotein (GP) Ib-IX-V surface receptor to the VWF A1 domain. Congenital mutations occurring in the A1 domain result in the clinical bleeding diathesis of several subtypes of Type 2 Von Willebrand Disease. These mutations can either enha...
Article
Because of its protein-denaturing ability, urea has played a pivotal role in the experimental and conceptual understanding of protein folding and unfolding. The measure of urea's ability to force a protein to unfold is given by the m value, an experimental quantity giving the free energy change for unfolding per molar urea. With the aid of Tanford'...
Article
Von Willebrand factor (VWF), a multimeric multidomain glycoprotein secreted into the blood from vascular endothelial cells, initiates platelet adhesion at sites of vascular injury. This process requires the binding of platelet glycoprotein Ib-IX-V to the A1 domain of VWF monomeric subunits under fluid shear stress. The A2 domain of VWF monomers con...
Article
Full-text available
A primary thermodynamic goal in protein biochemistry is to attain a predictive understanding of the energetic changes responsible for solvent-induced folding and unfolding. This chapter demonstrates the use of Tanford's transfer model to predict solvent-dependent cooperative protein folding/unfolding free energy changes (m values). This approach pr...
Article
Osmolytes that are naturally selected to protect organisms against environmental stresses are known to confer stability to proteins via preferential exclusion from protein surfaces. Solvophobicity, surface tension, excluded volume, water structure changes and electrostatic repulsion are all examples of forces proposed to account for preferential ex...
Article
See also Jin M, Cataland S, Bissell M, Wu HM. A rapid test for the diagnosis of thrombotic thrombocytopenic purpura using surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF)-mass spectrometry. This issue, pp 333–8.
Article
A primary thermodynamic goal in protein biochemistry is to attain predictive understanding of the detailed energetic changes that are responsible for folding/unfolding. Through use of recently determined free energies of side-chain and backbone transfer from water to osmolytes and Tanford's transfer model, we demonstrate that the long-sought goal o...

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Projects (2)
Project
Phase transitions of proteins
Project
Study the interactions of clinical VWF A1 mutants with Platelet receptor