4.5 Article

Ceramide channels: Influence of molecular structure on channel formation in membranes

期刊

BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
卷 1818, 期 5, 页码 1291-1301

出版社

ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2012.02.010

关键词

Ceramide; Analogs; Channels; Mitochondria; Permeabilization; Pore

资金

  1. National Science Foundation [MCB-1023008]
  2. National Institutes of Health [HL-083187]
  3. Veterans Administration
  4. Veteran's Administration REAP
  5. NCI [IPO1CA097132, P30 CA 138313]
  6. NIH/NCRR [P20 RR017677]
  7. NIH from National Center for Research Resources [C06 RR018823]
  8. Direct For Biological Sciences
  9. Div Of Molecular and Cellular Bioscience [1023008] Funding Source: National Science Foundation

向作者/读者索取更多资源

The sphingolipid, ceramide, self-assembles in the mitochondrial outer membrane (MOM), forming large channels capable of translocating proteins. These channels are believed to be involved in protein release from mitochondria, a key decision-making step in cell death. Synthetic analogs of ceramide, bearing modifications in each of the major structural features of ceramide were used to probe the molecular basis for the stability of ceramide channels. Channel stability and mitochondrial permeabilization were disrupted by methylation of the C1-hydroxyl group whereas modifications of the C3 allylic hydroxyl group were well tolerated. A change in chirality at C2 that would influence the orientation of the C1-hydroxyl group resulted in a strong reduction of channel-forming ability. Similarly, methylation of the amide nitrogen is also detrimental to channel formation. Many changes in the degree, location and nature of the unsaturation of ceramide had little effect on mitochondrial permeabilization. Competition experiments between ceramide and analogs resulted in synergy with structures compatible with the ceramide channel model and antagonism with incompatible structures. The results are consistent with ceramide channels being highly organized structures, stabilized by specific inter-molecular interactions, similar to the interactions responsible for protein folding. (C) 2012 Elsevier B.V. All rights reserved.

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