Conformational Stability and Domain Unfolding of the Von Willebrand Factor A Domains

Auton, Matthew; Crúz, Miguel A.; Moake, Joel L.

doi:10.1016/j.jmb.2006.10.067

Cited by 79 publications

(113 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We showed that each type 2B GOF mutation involved herein made A1 partially open. This is consistent with reports that a partial unfolding conformation of A1 has high affinity to GPIb␣ (16,29,40), because an open conformation of A1 may be in favor of unfolding, which may first occur at such weak regions as the ␤3␣2-loop and the ␣2-helix (52,53) (Figs. 7 and 8).…”

Section: Discussionsupporting

confidence: 92%

“…The newly increased populations in the sampled space might include the "activated" A1 conformation with high affinity to GPIb␣. As a result, a mutation may enhance the transition from a closed conformation to a partly open one in favor of binding to GPIb␣, consistent with the reports that a partial unfolding conformation of A1 has high affinity to GPIb␣ (16,29,40), but a combination of two type 2B mutations in a single construct does nothing for the affinity of binding to platelets (41).…”

Section: Gof Mutation Triggers the Switch From A Stable Conformation supporting

confidence: 85%

See 1 more Smart Citation

A Mechanism for Localized Dynamics-driven Affinity Regulation of the Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Liu

Fang

2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Gain of function (GOF) mutations enhance the vWF-GPIb␣ interaction. Results: GOF mutations induce destabilization of the N-terminal arm and increase mobility of the ␣2-helix. Conclusion: Dynamics-driven up-regulation of A1 affinity to GPIb␣ serves as a GOF mechanism of type 2B mutations. Significance: These results are helpful in understanding the structural basis of GOF mutants and in developing allosteric drugs against the activated A1 domain.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Gof Mutation Triggers the Switch From A Stable Conformation supporting

confidence: 85%

A Mechanism for Localized Dynamics-driven Affinity Regulation of the Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Liu

Fang

2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Chemical unfolding of PTMP1 using guanidine hydrochloride revealed a three-state transition with one apparent intermediate (Fig. 4d), and a conformational stability comparable with other proteins with VWA domains 26 . The isolated single VWA domains exhibited an overall lower structural stability against chemical denaturation than the fulllength protein.…”

Section: Resultsmentioning

confidence: 60%

Structural and functional features of a collagen-binding matrix protein from the mussel byssus

et al. 2014

View full text Add to dashboard Cite

Blue mussels adhere to surfaces by the byssus, a holdfast structure composed of individual threads representing a collagen fibre reinforced composite. Here, we present the crystal structure and function of one of its matrix proteins, the proximal thread matrix protein 1, which is present in the proximal section of the byssus. The structure reveals two von Willebrand factor type A domains linked by a two-b-stranded linker yielding a novel structural arrangement. In vitro, the protein binds heterologous collagens with high affinity and affects collagen assembly, morphology and arrangement of its fibrils. By providing charged surface clusters as well as insufficiently coordinated metal ions, the proximal thread matrix protein 1 might interconnect other byssal proteins and thereby contribute to the integrity of the byssal threads in vivo. Moreover, the protein could be used for adjusting the mechanical properties of collagen materials, a function likely important in the natural byssus.

show abstract

“…The proteins used in this study were drawn from those reported in studies by Myers et al and Hong et al, along with some we added (7,(29)(30)(31)(32)(33)(34)(35). The m values depend on salt concentration and pH, so only those proteins are included that are monomeric, denature reversibly in the presence of urea at neutral pH and moderate salt, exhibit two-state behavior, and contain no cofactor or metal ion.…”

Section: Discussionmentioning

confidence: 99%

Anatomy of energetic changes accompanying urea-induced protein denaturation

Auton

Holthauzen

Bolen

2007

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

Self Cite

264

401

View full text Add to dashboard Cite

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's transfer model [Tanford C (1964) J Am Chem Soc 86:2050 -2059], we use newly obtained group transfer free energies (GTFEs) of protein side-chain and backbone units from water to 1 M urea to account for the m value of urea, and the method reveals the anatomy of protein denaturation in terms of residue-level free energy contributions of groups newly exposed on denaturation. The GTFEs were obtained by accounting for solubility and activity coefficient ratios accompanying the transfer of glycine from water to 1 M urea. Contrary to the opinions of some researchers, the GTFEs show that urea does not denature proteins through favorable interactions with nonpolar side chains; what drives urea-induced protein unfolding is the large favorable interaction of urea with the peptide backbone. Although the m value is said to be proportional to surface area newly exposed on denaturation, only Ϸ25% of the area favorably contributes to unfolding (because of newly exposed backbone units), with Ϸ75% modestly opposing urea-induced denaturation (originating from side-chain exposure). Use of the transfer model and newly determined GTFEs achieves the long-sought goal of predicting urea-dependent cooperative protein unfolding energetics at the level of individual amino acid residues. m value ͉ transfer free energy ͉ transfer model ͉ activity coefficient ͉ self-avoiding random coil U nderstanding the energetics of protein-solute interactions is one of the most elusive goals of protein science, with urea-induced denaturation serving as a long-standing reminder of the inability to experimentally account for such fundamental interactions in a detailed manner. More than 40 years ago, Tanford set out to identify the sites and free energies of urea interaction with protein groups in enough detail to account for the energetics of urea-induced denaturation (1-3). In principle, the transfer model he developed provides a means of dissecting which groups (side chain and backbone) are involved in denaturation and how much they contribute to the free energy of denaturation by urea. For the transfer model (see Scheme 1) to be successful, two requirements must be met: (i) accurate transfer free energy changes for side-chain and backbone groups must be known, and (ii) the free energy of transfer of a native or denatured state of a protein from water to the urea solution must be equal to the sum of the transfer free energy contributions of its solvent-exposed parts. Of these two requirements, the ability to obtain accurate transfer free energies of side chains and backbone groups has been a particularly difficult impediment to quantifying the energetics of urea-induced denaturation. Here, we present results fo...

show abstract

Conformational Stability and Domain Unfolding of the Von Willebrand Factor A Domains

Cited by 79 publications

References 45 publications

A Mechanism for Localized Dynamics-driven Affinity Regulation of the Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

A Mechanism for Localized Dynamics-driven Affinity Regulation of the Binding of von Willebrand Factor to Platelet Glycoprotein Ibα

Structural and functional features of a collagen-binding matrix protein from the mussel byssus

Anatomy of energetic changes accompanying urea-induced protein denaturation

Contact Info

Product

Resources

About