Pulmonary surfactant‐associated polypeptide C in a mixed organic solvent transforms from a monomeric α‐helical state into insoluble β‐sheet aggregates

Szyperski, Thomas; Vandenbussche, Guy; Curstedt, Tore; Ruysschaert, Jean Marie; Wüthrich, Kurt; Johansson, Jan

doi:10.1002/pro.5560071206

Cited by 85 publications

(107 citation statements)

References 49 publications

(37 reference statements)

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“…The efficiency of folding of transmembrane helices correlates with their helical propensity in aqueous solution; poly-Leu segments are folded into compact, possibly helical, structure already in the translocon while poly-Val has a more extended conformation [42]. SP-C is highly inefficient in forming helical structure, in contrast to polyVal→polyLeu substituted variants [8,30,33,34]. It is therefore likely that formation of the proSP-C polyVal transmembrane helix is comparatively inefficient [24].…”

Section: Discussionmentioning

confidence: 99%

“…It is thus possible that the polyVal segment mediates proSP-C L188Q aggregation, and that in the CTC/proSP-C L188Q complex, CTC binds to the polyVal region of proSP-C. In order to test these hypotheses we next studied the effects of CTC on SP-C amyloid fibril formation (a process that requires unfolding of its α-helix [8]), CTC binding to non-helical SP-C, and the effects of replacing the polyVal region of proSP-C L188Q with a polyLeu sequence.…”

Section: Prosp-c L188q Aggregation After Transfection With Ctcmentioning

confidence: 99%

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Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

Nerelius

Martin

Peng

et al. 2008

Biochemical Journal

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International audienceThe newly synthesized surfactant protein C precursor (proSP-C) is an integral endoplasmic reticulum (ER) membrane protein with a single metastable polyVal α-helical transmembrane domain that comprises two thirds of the mature peptide. More than 20 mutations in the ER-lumenal, C-terminal domain of proSP-C (CTC), are associated with interstitial lung disease (ILD), and some of the mutations cause intracellular accumulation of cytotoxic protein aggregates and a corresponding decrease in mature SP-C. Here it is shown that (i) human embryonic kidney cells expressing the ILD associated mutants proSP-CL188Q and proSP-CΔExon4 accumulate Congo red positive amyloid-like inclusions, while cells transfected with the mutant proSP-CI73T do not, (ii) transfection of CTC into cells expressing proSP-CL188Q results in a stable CTC/proSP-CL188Q complex, increased proSP-CL188Q half life and reduced formation of Congo red positive deposits, (iii) replacement of the metastable polyVal transmembrane segment with a stable polyLeu likewise prevents formation of amyloid-like proSP-CL188Q aggregates, and (iv) binding of recombinant CTC to non-helical SP-C blocks SP-C amyloid fibril formation. These data suggest that CTC can prevent the polyVal segment of proSP-C from promoting formation of amyloid-like deposits during biosynthesis, by binding to non-helical conformations. Mutations in the Brichos domain of proSP-C may lead to ILD via loss of CTC chaperone function

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Section: Discussionmentioning

confidence: 99%

Section: Prosp-c L188q Aggregation After Transfection With Ctcmentioning

confidence: 99%

Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

Nerelius

Martin

Peng

et al. 2008

Biochemical Journal

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“…However, the SP-C transmembrane segment is composed essentially of polyvaline and therefore strongly favors a ␤-strand conformation. As a consequence, the SP-C helix is unable to refold into the helical structure once it has unfolded, and then instead aggregates (23). The insoluble, aggregated form of SP-C contains a ␤-sheet structure and shows abundant amyloid-like fibrils (24).…”

Section: Amyloidogenic Sequences Guarded By Dedicated Chaperone Domainsmentioning

confidence: 99%

Specific Chaperones and Regulatory Domains in Control of Amyloid Formation

Landreh

Rising

Presto

et al. 2015

Journal of Biological Chemistry

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Many proteins can form amyloid-like fibrils in vitro, but only about 30 amyloids are linked to disease, whereas some proteins form physiological amyloid-like assemblies. This raises questions of how the formation of toxic protein species during amyloidogenesis is prevented or contained in vivo. Intrinsic chaperoning or regulatory factors can control the aggregation in different protein systems, thereby preventing unwanted aggregation and enabling the biological use of amyloidogenic proteins. The molecular actions of these chaperones and regulators provide clues to the prevention of amyloid disease, as well as to the harnessing of amyloidogenic proteins in medicine and biotechnology.

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“…However, the relative position of the palmitoyl-cysteines in relation to the valine-rich "-helix is still uncertain as they In addition to its pronounced hydrophobicity, manipulation and studies of SP-C are further complicated by its structural instability. SP-C can transform irreversibly from a monomeric " helix into aggregated # sheets [131], which form amyloid fibrils [132]. # sheet formation is observed in vitro by the removal of the transmembrane domain from the phospholipid environment.…”

Section: Structure-function Relationships Of Sp-cmentioning

confidence: 99%

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

Mingarro¹,

Lukovic²,

Vilar³

et al. 2008

CMC

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Pulmonary surfactant is a lipid-protein complex that coats the interior of the alveoli and enables the lungs to function properly. Upon its synthesis, lung surfactant adsorbs at the interface between the air and the hypophase, a capillary aqueous layer covering the alveoli. By lowering and modulating surface tension during breathing, lung surfactant reduces respiratory work of expansion, and stabilises alveoli against collapse during expiration.Pulmonary surfactant deficiency, or dysfunction, contributes to several respiratory pathologies, such as infant respiratory distress syndrome (IRDS) in premature neonates, and acute respiratory distress syndrome (ARDS) in children and adults. The main clinical exogenous surfactants currently in use to treat some of these pathologies are essentially organic extracts obtained from animal lungs. Although very efficient, natural surfactants bear serious defects: i) they could vary in composition from batch to batch; ii) their production involves relatively high costs, and sources are limited; and iii) they carry a potential risk of transmission of animal infectious agents and the possibility of immunological reaction. All these caveats justify the necessity for a highly controlled synthetic material.In the present review the efforts aimed at new surfactant development, including the modification of existing exogenous surfactants by adding molecules that can enhance their activity, and the progress achieved in the production of completely new preparations, are discussed. Pulmonary surfactant function and dysfunctionThe respiratory surface of lungs constitutes the largest area of the human body exposed to the environment. Efficient gas exchange requires a large enough surface to be continuously exposed to air while minimising the barriers for oxygen and carbon dioxide to diffuse between air and the blood compartment [1]. At the same time, a selection of combined defence mechanisms is required to help keep such an essentially exposed area sterile of potential pathogenic microorganisms. Pulmonary surfactant, a lipid-protein complex produced by the alveolar epithelium of lungs, has been optimised to coordinate two main activities through natural evolution. On the one hand, it stabilises the respiratory surface against physical forces, therefore minimising the work required to maintain the large respiratory surface open to air [2][3][4]. On the other hand, pulmonary surfactant contains elements responsible for establishing a primary innate antipathogenic barrier, essential to ensure an intrinsically low pathogen load in the absence of induced defence mechanisms [5]. Extensive research in the last few decades has revealed some of the molecular mechanisms involved in pulmonary surfactant action. However, the manner in which both the biophysical and defence activities are intermingled and coordinately modulated in the alveolar spaces is now only beginning to be envisioned.Pulmonary surfactant is composed of approximately 90% lipids and 8-10% proteins, although only around 5% ...

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Pulmonary surfactant‐associated polypeptide C in a mixed organic solvent transforms from a monomeric α‐helical state into insoluble β‐sheet aggregates

Cited by 85 publications

References 49 publications

Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

Mutations linked to interstitial lung disease can abrogate anti-amyloid function of prosurfactant protein C

Specific Chaperones and Regulatory Domains in Control of Amyloid Formation

Synthetic Pulmonary Surfactant Preparations: New Developments and Future Trends

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