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Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1707-12. Epub 2002 Jan 22.

Cytosolic malate dehydrogenase confers selectivity of the nucleic acid-conducting channel.

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Division of Nephrology, Mt. Sinai School of Medicine, Box 1243, 1 Gustave L. Levy Place, New York, NY 10029, USA.


We have described previously a cell surface channel that is highly selective for nucleic acids. Nucleic acid conductance is 10 pS and the channel is at least 10,000-fold more selective for oligodeoxynucleotides than any anion tested (1). Herein we provide evidence that the nucleic acid-conducting channel (NACh) is a heteromultimeric complex of at least two proteins; a 45-kDa pore-forming subunit (p45) and a 36-kDa regulatory subunit (p36). Reconstitution of p45 in planar lipid bilayers resulted in formation of a channel which gated in the absence of nucleic acid and which was more selective for anions (including oligonucleotide) than cations. This channel exhibited transitions from one level of current to another (or to the closed state); however the incidence of transitions was rare. Channel activity was not observed when p36 was reconstituted alone. Reconstitution of p36 with p45 restored nucleic acid dependence and selectivity to the channel. Protein sequence analysis identified p36 as cytosolic malate dehydrogenase (cMDH). Experiments were performed to prove that cMDH is a regulatory subunit of NACh. Selective activity was observed when p45 was reconstituted with pig heart cMDH but not with mitochondrial MDH. Both the enzyme substrate l-malate and antiserum raised against cMDH block NACh activity. These data demonstrate that a nucleic acid conducting channel is a complex of at least two proteins, p45 and cMDH. Furthermore, these data establish that cMDH confers nucleic acid selectivity of the channel.

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