Navigation Links
Architecture of signaling proteins enhances knowledge of key receptors

DURHAM, N.C. -- A team of scientists from Duke Medicine, the University of Michigan and Stanford University has determined the underlying architecture of a cellular signaling complex involved in the body's response to stimuli such as light and pain.

This complex, consisting of a human cell surface receptor and its regulatory protein, reveals a two-step mechanism that has been hypothesized previously but not directly documented.

The findings, reported on June 22, 2014, in the journal Nature, provide structural images of a G-protein coupled receptor (GPCR) in action.

"It is crucial to visualize how these receptors work to fully appreciate how our bodies respond to a wide array of stimuli, including light, hormones and various chemicals," said co-senior author Robert J. Lefkowitz, M.D., the James B. Duke Professor of Medicine at Duke University School of Medicine and Howard Hughes Medical Institute investigator.

Lefkowitz is co-senior author with Georgios Skiniotis, Ph.D., the Jack E. Dixon Collegiate Professor at the Life Sciences Institute at the University of Michigan, and Brian K. Kobilka, M.D., the Helene Irwin Fagan Chair in Cardiology at Stanford University School of Medicine. Lefkowitz and Kobilka shared the 2012 Nobel Prize in Chemistry for their discoveries involving GPCRs.

GPCRs represent the largest family of drug targets for human diseases, including cardiovascular disorders, neurological ailments and various types of cancer. The protein beta arrestin is key for regulating these receptors, and the authors have visualized a complex of the protein beta arrestin along with the receptor involved in the "fight-or-flight" response in humans.

"Arrestin's primary role is to put the cap on GPCR signaling. Elucidating the structure of this complex is crucial for understanding how the receptors are desensitized in order to prevent aberrant signaling," Skiniotis said.

"High-resolution visualization of this signaling assembly is challenging because the protein complexes are transient and highly dynamic and large amounts of the isolated proteins are required for the experiments," said co-lead author Arun K. Shukla, who worked with Lefkowitz at Duke and is now setting up an independent laboratory in the Department of Biological Sciences and Bioengineering at the Indian Institute of Technology, Kanpur.

Once the authors had material available for direct structural visualization, they used electron microscopy to reveal how the individual molecules of this signaling assembly are organized with respect to each other.

The researchers then combined thousands of individual images to generate a better picture of the molecular architecture. They further clarified this picture by cross-linking analysis and mass spectrometry measurements.

The authors next aim to obtain greater detail about this assembly using X-ray crystallography, a technology that should reveal atomic level insights into this architecture. Such atomic details could then be used in experiments to design novel drugs and develop a better understanding of fundamental concepts in GPCR biology.

"This is just a start and there is a long way to go," Shukla said. "We have to visualize similar complexes of other GPCRs to develop a comprehensive understanding of this family of receptors."

In addition to Lefkowitz, Shukla, Skiniotis and Kobilka, study authors include Gerwin H. Westfield; Kunhong Xiao; Rosana I. Reis; Li-Yin Huang; Prachi Tripathi-Shukla; Jiang Qian; Sheng Li; Adi Blanc; Austin N. Oleskie; Anne M. Dosey; Min Su; Cui-Rong Liang; Ling-Ling Gu; Jin-Ming Shan; Xin Chen; Rachel Hanna; Minjung Choi; Xiao Jie Yao; Bjoern U. Klink; Alem W. Kahsai; Sachdev S. Sidhu; Shohei Koide; Pawel A. Penczek; Anthony A. Kossiakoff; and Virgil L. Woods Jr.

Howard Hughes Medical Institute provided funding, along with the National Institutes of Health (DK090165, NS028471, GM072688, GM087519, HL075443, HL16037 and HL70631); the Mathers Foundation; the Pew Scholars Program in Biomedical Sciences; the Canadian Institutes of Health Research; and Coordenao de Aperfeioamento de Pessoal de Nvel SuperiorCAPES.


Contact: Rachel Harrison
Duke University Medical Center

Related biology news :

1. Cell division speed influences gene architecture
2. RNA shows potential as boiling-resistant anionic polymer material for nanoarchitectures
3. Lightweight construction materials of highest stability thanks to their microarchitecture
4. Plant cell architecture: Growth toward a light source
5. Complex genetic architectures: Some common symptoms of trisomy 21
6. NREL researchers use imaging technologies to solve puzzle of plant architecture
7. Architecture of rod sensory cilium disrupted by mutation
8. Is it a rock, or is it Jell-O? Defining the architecture of rhomboid enzymes
9. Herbivores select on floral architecture in a South African bird-pollinated plant
10. Stem cells found to play restorative role when affecting brain signaling process
11. Geniposide protects hippocampal neurons via the non-classical estrogen signaling pathway
Post Your Comments:
Related Image:
Architecture of signaling proteins enhances knowledge of key receptors
(Date:10/29/2015)... , Oct. 29, 2015  The J. Craig ... report titled, "DNA Synthesis and Biosecurity: Lessons Learned and ... Department of Health and Human Services guidance for synthetic ... 2010. --> --> ... also has the potential to pose unique biosecurity threats. ...
(Date:10/29/2015)... Oct. 29, 2015  Rubicon Genomics, Inc., today ... distribution of its DNA library preparation products, including ... new ThruPLEX Plasma-seq kit. ThruPLEX Plasma-seq has been ... of NGS libraries for liquid biopsies--the analysis of ... prognostic applications in cancer and other conditions. Eurofins ...
(Date:10/29/2015)... , October 29, 2015 ... authentication company focused on the growing mobile commerce ... announces that StackCommerce, a leading marketplace to discover ... the Wocket® smart wallet on StackSocial for this ... ("NXT-ID" or the "Company"), a biometric authentication company ...
Breaking Biology News(10 mins):
(Date:11/25/2015)... ... November 25, 2015 , ... Jessica ... on AngelList early in their initial angel funding process. Now, they are paying ... looking to make early stage investments in the microbiome space. In this, ...
(Date:11/24/2015)... 24, 2015 /CNW/ - iCo Therapeutics ("iCo" or "the ... results for the quarter ended September 30, 2015. ... dollars and presented under International Financial Reporting Standards ... ," said Andrew Rae , President & ... are not only value enriching for this clinical ...
(Date:11/24/2015)... 24, 2015 --> ... report "Oligonucleotide Synthesis Market by Product & Services (Primer, ... Diagnostic, DNA, RNAi), End-User (Research, Pharmaceutical & Biotech, Diagnostic ... the market is expected to reach USD 1,918.6 Million ... a CAGR of 10.1% during the forecast period. ...
(Date:11/24/2015)... AVIV, Israel , Nov. 24, 2015  Tikcro Technologies Ltd. (OTCQB: ... held on December 29, 2015 at 11:00 a.m. Israel ... Co., Electra Tower, 98 Yigal Allon Street, 36 th Floor, ... election of Eric Paneth and Izhak Tamir to ... and Rami Skaliter as external directors; , approval of an amendment ...
Breaking Biology Technology: