Visual insight into how low pH alone can induce actin-severing ability in gelsolin under calcium-free conditions

Renu Garg, Nagesh Peddada, Amin Sagar, Deepak Nihalani, Ashish

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19 Scopus citations


Gelsolin is a key actin cytoskeleton-modulating protein primarily regulated by calcium and phosphoinositides. In addition, low pH has also been suggested to activate gelsolin in the absence of Ca2+ ions, although no structural insight on this pathway is available except for a reported decrement in its diffusion coefficient at low pH. We also observed ∼1.6-fold decrease in the molecular mobility of recombinant gelsolin when buffer pH was lowered from 9 to 5. Analysis of the small angle x-ray scattering data collected over the same pH range indicated that the radius of gyration and maximum linear dimension of gelsolin molecules increased from 30.3 to 34.1 Å and from 100 to 125 Å, respectively. Models generated for each dataset indicated that similar to the Ca2+-induced process, low pHalso promotes unwinding of this six-domain protein but only partially. It appeared that pH is able to induce extension of the G1 domain from the rest of the five domains, whereas the Ca2+-sensitive latch between G2 and G6 domains remains closed. Interestingly, increasing the free Ca2+ level to merely ∼40 nM, the partially open pH 5 shape "sprung open" to a shape seen earlier for this protein at pH 8 and 1 mM free Ca2+. Also, pH alone could induce a shape where the g3-g4 linker of gelsolin was open when we truncated the C-tail latch from this protein. Our results provide insight into how under physiological conditions, a drop in pH can fully activate the F-actin-severing shape of gelsolin with micromolar levels of Ca2+ available.

Original languageEnglish (US)
Pages (from-to)20387-20397
Number of pages11
JournalJournal of Biological Chemistry
Issue number23
StatePublished - Jun 10 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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