Core Sequence of PAPf39 Amyloid Fibrils and Mechanism of pH-Dependent Fibril Formation: The Role of Monomer Conformation

French, Kinsley C.; Makhatadze, George I.

doi:10.1021/bi301406d

Cited by 29 publications

(58 citation statements)

References 29 publications

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“…Our data for the L565-L597 region showed a relatively high degree of deuterium uptake (approximately 40%) compared to what is usually expected for amyloid cores 40 . However, cases with a higher degree of exchange have been described for amyloid fibrils 41 , and importantly we found the deuterium level in the A546T FAS1-4 fibril core to be stable during prolonged incubation. Thus, the relatively high uptake of deuterium in the fibril core of A546T FAS1-4 likely results from a combination of fibril dynamics and structural characteristics where a maturation of the fibril core is propagated from the central parts of the fibrils towards the ends creating a heterogeneous structure with a more loose packing of the fibril near the fibril extremities 42 .…”

Section: Discussionsupporting

confidence: 69%

Fibril Core of Transforming Growth Factor Beta-Induced Protein (TGFBIp) Facilitates Aggregation of Corneal TGFBIp

Sørensen¹,

Runager²,

Scavenius³

et al. 2015

Biochemistry

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Mutations in the transforming growth factor beta-induced (TGFBI) gene result in a group of hereditary diseases of the cornea that are collectively known as TGFBI corneal dystrophies. These mutations translate into amino acid substitutions mainly within the fourth fasciclin 1 domain (FAS1-4) of the transforming growth factor beta-induced protein (TGFBIp) and cause either amyloid or non-amyloid protein aggregates in the anterior and central parts of the cornea, depending on the mutation. The A546T substitution in TGFBIp causes lattice corneal dystrophy (LCD), which manifests as amyloid-type aggregates in the corneal stroma. We previously showed that the A546T substitution renders TGFBIp and the FAS1-4 domain thermodynamically less stable compared with the wild-type (WT) protein, and the mutant FAS1-4 is prone to amyloid formation in vitro. In the present study, we identified the core of A546T FAS1-4 amyloid fibrils. Significantly, we identified the Y571-R588 region of TGFBIp, which we previously found to be enriched in amyloid deposits in LCD patients. We further found that the Y571-R588 peptide seeded fibrillation of A546T FAS1-4 and, more importantly, we demonstrated that native TGFBIp aggregates in the presence of fibrils formed by the core peptide. Collectively, these data suggest an involvement of the Y571-R588 peptide in LCD pathophysiology.

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Section: Discussionsupporting

confidence: 69%

Fibril Core of Transforming Growth Factor Beta-Induced Protein (TGFBIp) Facilitates Aggregation of Corneal TGFBIp

Sørensen¹,

Runager²,

Scavenius³

et al. 2015

Biochemistry

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“…Seminal plasma contains factors that enhance HIV transmission (22,39) and others that may interfere with microbicide activity (21). Previous microbicide evaluations showed that PRO 2000 gel protected mice from HSV-2 transmission.…”

Section: Discussionmentioning

confidence: 99%

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Scott

Park

Dezzutti

2016

Antimicrob Agents Chemother

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cBroadly neutralizing monoclonal antibodies (nAbs) specific for HIV are being investigated for use in HIV prevention. Due to their ability to inhibit HIV attachment to and entry into target cells, nAbs may be suitable for use as topical HIV microbicides. As such, they would present an alternative intervention for individuals who may not benefit from using antiretroviral-based products for HIV prevention. We theorize that nAbs can inhibit viral transmission through mucosal tissue, thus reducing the incidence of HIV infection. The efficacy of the PG9, PG16, VRC01, and 4E10 antibodies was evaluated in an ex vivo human model of mucosal HIV transmission. nAbs reduced HIV transmission, causing 1.5-to 2-log 10 reductions in HIV replication in ectocervical tissues and Ϸ3-log 10 reductions in HIV replication in colonic tissues over 21 days. These antibodies demonstrated greater potency in colonic tissues, with a 50-fold higher dose being required to reduce transmission in ectocervical tissues. Importantly, nAbs retained their potency and reduced viral transmission in the presence of whole semen. No changes in tissue viability or immune activation were observed in colonic or ectocervical tissue after nAb exposure. Our data suggest that topically applied nAbs are safe and effective against HIV infection of mucosal tissue and support further development of nAbs as a topical microbicide that could be used for anal as well as vaginal protection.

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“…Peptide Purification-PAPf39 peptide NH 2 -GIHKQKEKSR-LQGGVLVNEILNHMKRATQIPSYKKLIMY-COOH (6,28,29) was synthesized at the Penn State College of Medicine Macromolecular Core Facility. PAPf39 was dissolved in 0.05% TFA and purified on a C18 reverse-phase HPLC column (Discovery Bio Wide pore C18 10 m, 25 cm ϫ 10 mm; Supelco SigmaAldrich, Bellefonte, PA) using a methanol gradient in the presence of 0.05% TFA.…”

Section: Methodsmentioning

confidence: 99%

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection

LoRicco

Neidleman

et al. 2016

Journal of Biological Chemistry

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Recent in vitro studies have demonstrated that amyloid fibrils found in semen from healthy and HIV-infected men, as well as semen itself, can markedly enhance HIV infection rates. Semen fibrils are made up of multiple naturally occurring peptide fragments derived from semen. The best characterized of these fibrils are SEVI (semen-derived enhancer of viral infection), made up of residues 248 -286 of prostatic acidic phosphatase, and the SEM1 fibrils, made up of residues 86 -107 of semenogelin 1. A small molecule screen for antagonists of semen fibrils identified four compounds that lowered semen-mediated enhancement of HIV-1 infectivity. One of the four, gallic acid, was previously reported to antagonize other amyloids and to exert anti-inflammatory effects. To better understand the mechanism by which gallic acid modifies the properties of semen amyloids, we performed biophysical measurements (atomic force microscopy, electron microscopy, confocal microscopy, thioflavin T and Congo Red fluorescence assays, zeta potential measurements) and quantitative assays on the effects of gallic acid on semen-mediated enhancement of HIV infection and inflammation. Our results demonstrate that gallic acid binds to both SEVI and SEM1 fibrils and modifies their surface electrostatics to render them less cationic. In addition, gallic acid decreased semen-mediated enhancement of HIV infection but did not decrease the inflammatory response induced by semen. Together, these observations identify gallic acid as a non-polyanionic compound that inhibits semen-mediated enhancement of HIV infection and suggest the potential utility of incorporating gallic acid into a multicomponent microbicide targeting both the HIV virus and host components that promote viral infection.Amyloid fibrils are ordered protein aggregates associated with a large number of human diseases, many of which are neurodegenerative in nature, such as Alzheimer disease and Parkinson disease (1-3). They are characterized by their cross-␤ structure, with ␤ sheets running perpendicular to the fibril axis, and by their ability to bind to certain fluorescent dyes, such as thioflavin T (ThT), 4 whose fluorescence intensity increases considerably upon binding to amyloid fibrils.Amyloid fibrils are also found in semen from young, healthy men (4). Whether these fibrils serve a physiological function is not known, but they have been shown to markedly increase infection by a variety of sexually transmitted viruses, most notably HIV-1 (5-7). Under limiting dilution conditions, semen fibrils can increase HIV infection rates by up to 5 orders of magnitude (6). These fibrils are made up of naturally occurring peptide fragments in semen (6, 8 -10). The best characterized semen fibril is made up of a 39-residue fragment from human prostatic acid phosphatase (PAPf39) and has been termed SEVI (semen-derived enhancer of viral infection) (6). More recently, a second set of semen fibrils was identified from prostate-specific antigen-generated fragments of semenogelin (referred to collectivel...

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Core Sequence of PAPf39 Amyloid Fibrils and Mechanism of pH-Dependent Fibril Formation: The Role of Monomer Conformation

Cited by 29 publications

References 29 publications

Fibril Core of Transforming Growth Factor Beta-Induced Protein (TGFBIp) Facilitates Aggregation of Corneal TGFBIp

Fibril Core of Transforming Growth Factor Beta-Induced Protein (TGFBIp) Facilitates Aggregation of Corneal TGFBIp

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Gallic Acid Is an Antagonist of Semen Amyloid Fibrils That Enhance HIV-1 Infection

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