+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Near-membrane ensemble elongation in the proline-rich LRP6 intracellular domain may explain the mysterious initiation of the Wnt signaling pathway

Near-membrane ensemble elongation in the proline-rich LRP6 intracellular domain may explain the mysterious initiation of the Wnt signaling pathway

Bmc Bioinformatics 12(Suppl. 13): S13

LRP6 is a membrane protein crucial in the initiation of canonical Wnt/β-catenin signalling. Its function is dependent on its proline-serine rich intracellular domain. LRP6 has five PPP(S/T)P motifs that are phosphorylated during activation, starting with the site closest to the membrane. Like all long proline rich regions, there is no stable 3D structure for this isolated, contiguous region. In our study, we use a computational simulation tool to sample the conformational space of the LRP6 intracellular domain, under the spatial constraints imposed by (a) the membrane and (b) the close approach of the neighboring intracellular molecular complex, which is assembled on Frizzled when Wnt binds to both LRP6 and Frizzled on the opposite side of the membrane. We observe that an elongated form dominates in the LRP6 intracellular domain structure ensemble. This elongation could relieve conformational auto-inhibition of the PPP(S/T)PX(S/T) motif binding sites and allow GSK3 and CK1 to approach their phosphorylation sites, thereby activating LRP6 and the downstream pathway. We propose a model in which the conformation of the LRP6 intracellular domain is elongated before activation. This is based on the intrusion of the Frizzled complex into the ensemble space of the proline rich region of LRP6, which alters the shape of its available ensemble space. To test whether this observed ensemble conformational change is sequence dependent, we did a control simulation with a hypothetical sequence with 50% proline and 50% serine in alternating residues. We confirm that this ensemble neighbourhood-based conformational change is independent of sequence and conclude that it is likely found in all proline rich sequences. These observations help us understand the nature of proline rich regions which are both unstructured and which seem to evolve at a higher rate of mutation, while maintaining sequence composition.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 054560010

Download citation: RISBibTeXText

PMID: 22372892

DOI: 10.1186/1471-2105-12-s13-s13

Related references

Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling. Journal of Biological Chemistry 277(24): 21561-6, 2002

SHIP2 is Recruited to the Cell Membrane via its Proline-Rich Domain upon M-CSF Stimulation and Regulates M-CSF-Induced Signaling. FASEB Journal 18(4-5): Abst 337 20, 2004

Titin as a giant signaling molecule in the SH3 pathway Interaction of SH3 domain with the proline-rich titin PEVK segment. Biophysical Journal 86(1): 570a-571a, 2004

Structural basis of Robo proline-rich motif recognition by the srGAP1 Src homology 3 domain in the Slit-Robo signaling pathway. Journal of Biological Chemistry 281(38): 28430-7, 2006

Phosphorylation of PPP(S/T)P motif of the free LRP6 intracellular domain is not required to activate the Wnt/beta-catenin pathway and attenuate GSK3beta activity. Journal of Cellular Biochemistry 108(4): 886-895, 2010

A novel serine/proline-rich domain in combination with a transmembrane domain is required for the insertion of AtTic40 into the inner envelope membrane of chloroplasts. Plant Journal 52(5): 824-838, 2007

The intracellular proline-rich region of ActRIIB is important for activin signaling. Molecular & Cellular Endocrinology 180(1-2): 196, 2001

The unique proline-rich domain of parotid proline-rich proteins functions in secretory sorting. Journal of Cell Science 109: 1637-1645, 1996

Oligomerisation of the developmental regulator proline rich homeodomain (PRH/Hex) is mediated by a novel proline-rich dimerisation domain. Journal of Molecular Biology 358(4): 943-962, 2006

The GYF domain is a novel structural fold that is involved in lymphoid signaling through proline-rich sequences. Nature Structural Biology 6(7): 656-660, 1999

Proline-rich Akt substrate of 4 kDa PRAS4 A Novel Downstream Target of PI3k/Akt Signaling Pathway. 2011

Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway. Cellular Signalling 24(1): 17-24, 2012

A tobacco gene family for flower cell wall proteins with a proline-rich domain and a cysteine-rich domain. Proceedings of the National Academy of Sciences of the United States of America 90(14): 6829-6833, 1993

Effect of cytostatic proline rich polypeptide-1 on tumor suppressors of inflammation pathway signaling in chondrosarcoma. Molecular and Clinical Oncology 5(5): 618-624, 2016

Domain structure and function of rabbit histidine-proline-rich glycoprotein Is the his-pro-rich domain a pH-sensor?. FASEB Journal 9(6): A1465, 1995