Understanding single-pass transmembrane receptor signaling from a structural viewpoint—what are we missing?

TY - JOUR

T1 - Understanding single-pass transmembrane receptor signaling from a structural viewpoint—what are we missing?

AU - Bugge, Katrine Østergaard

AU - Lindorff-Larsen, Kresten

AU - Kragelund, Birthe Brandt

N1 - © 2016 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Single-pass transmembrane receptors are involved in essential processes of both physiological and pathological nature and represent more than 1300 proteins in the human genome. Despite the high biological relevance of these receptors, the mechanisms of the signal transductions they facilitate are incompletely understood. One major obstacle is the lack of structures of the transmembrane domains that connect the extracellular ligand-binding domains to the intracellular signaling platforms. Over a period of almost 20 years since the first structure was reported, only 21 of these receptors have become represented by a transmembrane domain structure. This scarceness stands in strong contrast to the significance of these transmembrane α-helices for receptor functionality. In this review, we explore the properties and qualities of the current set of structures, as well as the methodological difficulties associated with their characterization and the challenges left to be overcome. Without an increased and focused effort to bring this class of proteins on par with the remaining membrane protein field, a serious lag in their biological understanding looms. Design of pharmaceutical agents, prediction of mutational affects in relation to disease, and deciphering of functional mechanisms require high-resolution structural information, especially when dealing with a domain carrying so much functionality in so few residues.

AB - Single-pass transmembrane receptors are involved in essential processes of both physiological and pathological nature and represent more than 1300 proteins in the human genome. Despite the high biological relevance of these receptors, the mechanisms of the signal transductions they facilitate are incompletely understood. One major obstacle is the lack of structures of the transmembrane domains that connect the extracellular ligand-binding domains to the intracellular signaling platforms. Over a period of almost 20 years since the first structure was reported, only 21 of these receptors have become represented by a transmembrane domain structure. This scarceness stands in strong contrast to the significance of these transmembrane α-helices for receptor functionality. In this review, we explore the properties and qualities of the current set of structures, as well as the methodological difficulties associated with their characterization and the challenges left to be overcome. Without an increased and focused effort to bring this class of proteins on par with the remaining membrane protein field, a serious lag in their biological understanding looms. Design of pharmaceutical agents, prediction of mutational affects in relation to disease, and deciphering of functional mechanisms require high-resolution structural information, especially when dealing with a domain carrying so much functionality in so few residues.

U2 - 10.1111/febs.13793

DO - 10.1111/febs.13793

M3 - Review

C2 - 27350538

SN - 1742-464X

VL - 283

SP - 4424

EP - 4451

JO - The FEBS Journal

JF - The FEBS Journal

IS - 24

ER -