Self-Assembling Amphiphiles for Construction of Protein Molecular Architecture

Yu, Ying‐Ching; Berndt, Peter; Tirrell, Matthew; Fields, Gregg B.

doi:10.1021/ja9627656

Cited by 278 publications

(325 citation statements)

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“…Preparation of Peptide and Peptide Amphiphile Ligands-Peptide resin assembly was performed on an Applied Biosystems 433A peptide synthesizer using 9-fluorenylmethoxycarbonyl solid phase methodology, as previously described (50,51). All of the standard peptide synthesis chemicals and solvents were analytical grade or better.…”

Section: Methodsmentioning

confidence: 99%

Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by α2β1 Integrin and CD44 Triple-helical Ligands Derived from Type IV Collagen

Baronas-Lowell

Lauer‐Fields

Borgia³

et al. 2004

Journal of Biological Chemistry

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Tumor cell binding to components of the basement membrane is well known to trigger intracellular signaling pathways. Signaling ultimately results in the modulation of gene expression, facilitating metastasis. Type IV collagen is the major structural component of the basement membrane and is known to be a polyvalent ligand, possessing sequences bound by the ␣ 1 ␤ 1 , ␣ 2 ␤ 1 , and ␣ 3 ␤ 1 integrins, as well as cell surface proteoglycan receptors, such as CD44/chondroitin sulfate proteoglycan (CSPG). The role of ␣ 2 ␤ 1 integrin and CD44/CSPG receptor binding on human melanoma cell activation has been evaluated herein using triple-helical peptide ligands incorporating the ␣1(IV)382-393 and ␣1(IV)1263-1277 sequences, respectively. Gene expression and protein production of matrix metalloproteinases-1 (MMP-1), -2, -3, -13, and -14 were modulated with the ␣ 2 ␤ 1 -specific sequence, whereas the CD44-specific sequence yielded significant stimulation of MMP-8 and lower levels of modulation of MMP-1, -2, -13, and -14. Analysis of enzyme activity confirmed different melanoma cell proteolytic potentials based on engagement of either the ␣ 2 ␤ 1 integrin or CD44/CSPG. These results are indicative of specific activation events that tumor cells undergo upon binding to select regions of basement membrane collagen. Based on the present study, triple-helical peptide ligands provide a general approach for monitoring the regulation of proteolysis in cellular systems.Melanoma is one of the most rapidly increasing malignancies in the world in both young and old patients, with over 50,000 newly diagnosed patients each year (1). 1 Mortality from cancer is frequently due to metastasis, given that surgical excision of the primary tumor considerably enhances the prognosis of a patient and prolongs survival (2). Metastasis is a complex series of finely coordinated events that results in cancer cells circulating in lymph and blood vascular systems to invade remote tissues and establish secondary sites of tumor growth (3). Extravasation of the tumor cell into secondary tissues requires alterations in cellular behaviors, resulting from specific adhesion to components of the basement membrane. Tumor cells respond to each of the various components of the ECM, 2 including the collagens; noncollagenous glycoproteins, such as fibronectin and laminin; and proteoglycans, such as decorin and syndecan (4). These interactions are known to occur through several families of cell surface receptors, including the integrins and cell surface proteoglycans.Integrins are heterodimeric proteins composed of one ␣ and one ␤ subunit and are the best described of the cell surface adhesion molecules. To date, there are 18 different ␣ subunits and 8 distinct ␤ subunits identified that combine to form at least 24 heterodimers (5-7). Although the specific integrin expression profile can fluctuate with tumor type and stage of progression, highly metastatic melanoma cells are known to up-regulate expression of, and ␣ 6 ␤ 4 integrins while down-regulating the expression ...

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Section: Methodsmentioning

confidence: 99%

Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by α2β1 Integrin and CD44 Triple-helical Ligands Derived from Type IV Collagen

Baronas-Lowell

Lauer‐Fields

Borgia³

et al. 2004

Journal of Biological Chemistry

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“…Depending on the composition, amphiphilic peptides have been shown to organize peptide secondary structure and aggregation state (27)(28)(29)(30). PAs synthesized previously with mono-or di-alkyl tails were found to associate in conformations such as triple helical structures found in collagen (31)(32)(33)(34)(35)(36)(37)(38). Modification of this strategy allowed us to design a cone-shaped, ionic amphiphile that could assemble into cylindrical micelles or peptide nanofibers (17).…”

mentioning

confidence: 99%

Peptide-amphiphile nanofibers: A versatile scaffold for the preparation of self-assembling materials

Hartgerink

Beniash

Stupp

2002

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

1,166

950

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Twelve derivatives of peptide-amphiphile molecules, designed to self-assemble into nanofibers, are described. The scope of amino acid selection and alkyl tail modification in the peptide-amphiphile molecules are investigated, yielding nanofibers varying in morphology, surface chemistry, and potential bioactivity. The results demonstrate the chemically versatile nature of this supramolecular system and its high potential for manufacturing nanomaterials. In addition, three different modes of self-assembly resulting in nanofibers are described, including pH control, divalent ion induction, and concentration. P reprogrammed noncovalent bonds, within and between molecules, build highly functional and dynamic structures in biology, which motivates our interest in self-assembly of synthetic systems. Over the past few decades a substantial amount of literature describing noncovalent self-assembly of nanostructures has accumulated (1-14). However, it is still difficult to design supramolecular structures, particularly if we want to start with designed molecules and form objects that measure between nanoscopic and macroscopic dimensions. Developing this ability will take us closer to the broad, bottom-up approach of selfassembly observed in biology.Our laboratory has studied over the past decade self-assembly of designed molecules into macromolecular structures of twodimensional (15, 16), one-dimensional (17, 18), and zerodimensional nature (19)(20)(21)(22). These self-assembled objects contain between 10 1 and 10 5 molecules and thus resemble synthetic and biological polymers in molar mass. The interactions that lead to the formation of these structures include chiral dipole-dipole interactions, -stacking, hydrogen bonds, nonspecific van der Waals interactions, hydrophobic forces, electrostatic interactions, and repulsive steric forces. All systems studied involved combinations of these forces that counterbalance the enormous translational and rotational entropic cost caused by polymolecular aggregation. In some cases the possibility of internally linking these self-assembled structures through covalent bonds has been explored (1,17,20,23). A cross-linking produces actual polymers whose various shapes and dimensionalities are controlled by self-assembly and are very different from the well-known ''beads-on-a-chain'' structures of traditional polymers.In our studies of self-assembling systems we also have explored self-organization at length scales much greater than those of the aggregates themselves, reaching into scales of microns, millimeters, and even centimeters. We also have been interested in functionalities that emerge from self-assembly at these largerlength scales. An interesting example was the layering and polar stacking of mushroom-shaped supramolecular structures each measuring about 5 nm. The stem-to-cap layers of these nanostructures result in centimeter-scale films that are spontaneously piezoelectric (24). The search for useful systems in the microscopic and macroscopic regime that take advantage of mole...

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“…The synthesis and purification of ␣1(I-III)Gly⌿{PO 2 H-CH 2 }Leu THPI (C 6 -Gly-Pro-Flp-(Gly-Pro-Hyp) 4 -Gly-Pro-Gln-Gly⌿{PO 2 H-CH 2 }-(RS)-Leu-Ala-Gly-Gln-Arg-Gly-Ile-Arg-(Gly-Pro-Hyp) 4 -GlyPro-Flp-NH 2 ) proceeded as for ␣1(V)Gly⌿{PO 2 H-CH 2 }Val THPI (26). The synthesis and purification of ␣1(I)715-721 THP ((Gly-Pro-Hyp) 4 -Gly-Ala-Hyp-Gly-Ala-Hyp-Gly-SerGln-Gly-Ala-Hyp-(Gly-Pro-Hyp) 3 -Gly-Pro-Tyr-NH 2 ) proceeded as for other THPs (31)(32)(33)(34).…”

Section: Methodsmentioning

confidence: 99%

Selective Modulation of Matrix Metalloproteinase 9 (MMP-9) Functions via Exosite Inhibition

Lauer‐Fields

Whitehead

et al. 2008

Journal of Biological Chemistry

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Unregulated activities of the matrix metalloproteinase (MMP) family have been implicated in primary and metastatic tumor growth, angiogenesis, and pathological degradation of extracellular matrix components, such as collagen and laminin. However, clinical trials with small molecule MMP inhibitors have been largely unsuccessful, with a lack of selectivity considered particularly problematic. Enhanced selectivity could be achieved by taking advantage of differences in substrate secondary binding sites (exosites) within the MMP family. In this study, triple-helical substrates and triple-helical transition state analog inhibitors have been utilized to dissect the roles of potential exosites in MMP-9 collagenolytic behavior. Substrate and inhibitor sequences were based on either the ␣1(V)436 -450 collagen region, which is hydrolyzed at the Gly2Val bond selectively by MMP-2 and MMP-9, or the Gly2Leu cleavage site within the consensus interstitial collagen sequence ␣1(I-III)769 -783, which is hydrolyzed by MMP-1, MMP-2, MMP-8, MMP-9, MMP-13, and MT1-MMP. Exosites within the MMP-9 fibronectin II inserts were found to be critical for interactions with type V collagen model substrates and inhibitors and to participate in interactions with an interstitial (types I-III) collagen model inhibitor. A triple-helical peptide incorporating a fibronectin II insert-binding sequence was constructed and found to selectively inhibit MMP-9 type V collagen-based activities compared with interstitial collagen-based activities. This represents the first example of differential inhibition of collagenolytic activities and was achieved via an exosite-binding triple-helical peptide.Collagen catabolism (collagenolysis) is normally a well regulated physiological process critical to tissue and organ development, morphogenesis, and wound healing (1). Pathological conditions resulting from aberrant collagenolysis include primary and metastatic tumor growth, arthritis, arteriosclerosis, and periodontitis (1-4). A number of proteases have been described as exhibiting collagenolytic behavior, requiring that they catalyze the hydrolysis of the collagen triple helix (1). The most extensively studied are the matrix metalloproteinases (MMPs).2 MMPs that catalyze the hydrolysis of one or more of the interstitial collagens (types I-III) within their triple-helical domain include the secreted proteases MMP-1, MMP-2, MMP-8, MMP-9, and MMP-13 and the membrane-bound proteases MT1-MMP and MT2-MMP (5-8).Considerable work has been performed to define the MMP domains and regions that participate in collagenolysis. In the cases of MMP-1, MMP-8, MMP-13, MT1-MMP, and MT2-MMP, efficient collagenolytic activity in the isolated enzyme requires both the catalytic (CAT) and hemopexin (HPX)-like domains ( Fig. 1) (9 -14). The linker region between these domains also participates in collagenolysis, either by direct binding of substrate (15) or by allowing for the proper orientation of the CAT and HPX domains (16). The "gelatinase" members of the MMP family (MMP-2 and MMP-9)...

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Self-Assembling Amphiphiles for Construction of Protein Molecular Architecture

Cited by 278 publications

References 63 publications

Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by α2β1 Integrin and CD44 Triple-helical Ligands Derived from Type IV Collagen

Differential Modulation of Human Melanoma Cell Metalloproteinase Expression by α2β1 Integrin and CD44 Triple-helical Ligands Derived from Type IV Collagen

Peptide-amphiphile nanofibers: A versatile scaffold for the preparation of self-assembling materials

Selective Modulation of Matrix Metalloproteinase 9 (MMP-9) Functions via Exosite Inhibition

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