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Structure and influence on stability and activity of the N‐terminal propeptide part of lung surfactant protein C
Author(s) -
Li Jing,
Liepinsh Edvards,
Almlén Andreas,
Thyberg Johan,
Curstedt Tore,
Jörnvall Hans,
Johansson Jan
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2006.05124.x
Subject(s) - pulmonary surfactant , protein precursor , terminal (telecommunication) , lung , chemistry , medicine , biochemistry , computer science , gene , telecommunications
Mature lung surfactant protein C (SP‐C) corresponds to residues 24–58 of the 21 kDa proSP‐C. A late processing intermediate, SP‐C i , corresponding to residues 12–58 of proSP‐C, lacks the surface activity of SP‐C, and the SP‐C i α‐helical structure does not unfold in contrast to the metastable nature of the SP‐C helix. The NMR structure of an analogue of SP‐C i , SP‐C i (1–31), with two palmitoylCys replaced by Phe and four Val replaced by Leu, in dodecylphosphocholine micelles and in ethanol shows that its α‐helix vs. that of SP‐C is extended N‐terminally. The Arg‐Phe part in SP‐C i that is cleaved to generate SP‐C is localized in a turn structure, which is followed by a short segment in extended conformation. Circular dichroism spectroscopy of SP‐C i (1–31) in microsomal or surfactant lipids shows a mixture of helical and extended conformation at pH 6, and a shift to more unordered structure at pH 5. Replacement of the N‐terminal hexapeptide segment SPPDYS (known to constitute a signal in intracellular targeting) of SP‐C i with results in a peptide that is mainly unstructured, independent of pH, in microsomal and surfactant lipids. Addition of a synthetic dodecapeptide, corresponding to the propeptide part of SP‐C i , to mature SP‐C results in slower aggregation kinetics and altered amyloid fibril formation, and reduces the surface activity of phospholipid‐bound SP‐C. These data suggest that the propeptide part of SP‐C i prevents unfolding by locking the N‐terminal part of the helix, and that acidic pH results in structural disordering of the region that is proteolytically cleaved to generate SP‐C.