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Nanoscale organization of hedgehog is essential for long-range signaling

Mayor , S and Sowdhamini , S and Shashidhara, R and VijayRaghavan, K. L. and Vyas, N and Goswami, D. A. and Manonmani, A and Sharma, P and Ranganath, H. A. (2008) Nanoscale organization of hedgehog is essential for long-range signaling. cell, 133 . pp. 1214-1227.

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Hedgehog (Hh) plays crucial roles in tissue-patterning and activates signaling in Patched (Ptc)-expressing cells. Paracrine signaling requires release and transport over many cell diameters away by a process that requires interaction with heparan sulfate proteoglycans (HSPGs). Here, we examine the organization of functional, fluorescently tagged variants in living cells by using optical imaging, FRET microscopy, and mutational studies guided by bioinformatics prediction. We find that cell-surface Hh forms suboptical oligomers, further concentrated in visible clusters colocalized with HSPGs. Mutation of a conserved Lys in a predicted Hh-protomer interaction interface results in an autocrine signaling-competent Hh isoform--incapable of forming dense nanoscale oligomers, interacting with HSPGs, or paracrine signaling. Thus, Hh exhibits a hierarchical organization from the nanoscale to visible clusters with distinct functions.

Item Type:Article
Subjects:Biomedical Science > Nanoscale biological processes
Divisions:Faculty of Medicine, Health and Life Sciences > School of Biological Sciences
ID Code:4082
Deposited By:JNCASR
Deposited On:02 Feb 2009 04:42
Last Modified:03 Mar 2009 17:32

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