Project 3

Physiological role of aGPCR autoproteolysis

Robert J. Kittel, University of Würzburg & Tobias Langenhan, Leipzig University

Team members
Nadine Ehmann
Matthias Nieberler
Alexander Grotemeyer
Chonglin Guan

Project Description
Auto-proteolysis is a phenomenon prevalent in Adhesion-GPCRs (aGPCRs). The GPCR proteolysis site (GPS), the location of self-cleavage, is embedded within the extracellular GAIN domain of every aGPCR and located close to the membrane. At an early phase of receptor biosynthesis the GAIN domain catalyzes proteolytic cleavage of an aGPCR pro-receptor into two separate polypeptide chains, NTF and CTF (N- and C-terminal fragments) in the endoplasmic reticulum. Further, the cleavage fragments of an aGPCR re-associate via the broken GAIN domain into a heterodimer and seemingly reconstitute the nascent receptor structure (homogeneric heterodimerisation). This peculiar type of protein maturation is thought to carry biological impact due to its evolutionary conservation. While some evidence suggests that GAIN cleavage is necessary for membrane targeting, other results indicate that NTF/CTF separation and NTF::CTF re-hybridzation are essential steps of the signalling cascade initiated through aGPCRs. Intriguingly, even cross-hybridization of NTF and CTF derived from different aGPCR homologs (heterogeneric heterodimerisation) was proposed to be feasible, and might enable porting of extracellular stimuli to different intracellular signalling routes. However, while previous investigations have established biochemical properties of aGPCR homo- and heterogeneric heterodimerisation, direct evidence of naturally formed aGPCR chimeras remains elusive. This project will address salient questions regarding the occurrence and physiological importance of aGPCR heterodimer formation using in vitro and in vivo models combined with nanoscopical imaging.

Publications

Scholz N*, Guan C*, Nieberler M*, Grotemeyer A*, Maiellaro I, Gao S, Beck S, Pawlak M, Sauer M, Asan E, Rothemund S, Winkler J, Prömel S, Nagel G, Langenhan T#, Kittel RJ# (2017) Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons. eLife (accepted for publication)

Kittel RJ#, Heckmann M# (2016) Synaptic Vesicle Proteins and Active Zone Plasticity. Front Synaptic Neurosci. 8:8. 

Langenhan T#, Piao X#, Monk KR# (2016) Adhesion G protein-coupled receptors in nervous system development and disease. Nature Reviews Neuroscience 17:550-61.

Maiellaro I#, Lohse MJ, Kittel RJ#, Calebiro D# (2016) cAMP Signals in Drosophila Motor Neurons Are Confined to Single Synaptic Boutons. Cell Reports 17:1238-1246. 

Nieberler M, Kittel RJ, Petrenko AG, Lin HH#, Langenhan T# (2016) Control of Adhesion GPCR Function Through Proteolytic Processing. Handbook of Experimental Pharmacology 234:83-109. 

Riemensperger T, Kittel RJ, Fiala A (2016) Optogenetics in Drosophila Neuroscience. In Bacterial Persistence. Methods Mol Biol. 1408:167-75. 

Scholz N#, Monk KR, Kittel RJ, Langenhan T# (2016) Adhesion GPCRs as a Putative Class of Metabotropic Mechanosensors. Handbook of Experimental Pharmacology 234:221-247. 

Beck K, Ehmann N, Andlauer TF, Ljaschenko D, Strecker K, Fischer M, Kittel RJ, Raabe T (2015) Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons. Dis Model Mech. 8:1389-400.

Monk K, Hamann JLangenhan T, Nijmeijer S, Schöneberg T, and Liebscher I (2015) Adhesion GPCRs: From In Vitro Pharmacology to In Vivo Mechanisms. Molecular Pharmacology 88:617-623. 

Langenhan T#, Barr MM, Bruchas MR, Ewer J, Griffith LC, Maiellaro I, Taghert PH, White BH, Monk KR# (2015) Model Organisms in GPCR Research. Molecular Pharmacology 88:596-603.  

Scholz N, Gehring J, Guan C, Ljaschenko D, Fischer R, Lakshmanan V, Kittel RJ#, Langenhan T# (2015) The Adhesion GPCR Latrophilin/CIRL Shapes Mechanosensation. Cell Reports 11:866-874.

Hamann J*,#, Aust G*, Arac D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin H-H, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T*, Schiöth HB*,# (2015) International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein-Coupled Receptors. Pharmacological Reviews 67:338–367.