scholarly journals Role of the Proline-rich Domain of Dynamin-2 and Its Interactions with Src Homology 3 Domains during Endocytosis of the AT1Angiotensin Receptor

2002 ◽  
Vol 277 (24) ◽  
pp. 21650-21656 ◽  
Author(s):  
Márta Szaszák ◽  
Zsuzsanna Gáborik ◽  
Gábor Turu ◽  
Peter S. McPherson ◽  
Adrian J. L. Clark ◽  
...  
Keyword(s):  
Src Homology 3 ◽  
Rich Domain ◽  
Src Homology ◽  
Dynamin 2

scholarly journals Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle

2021 ◽  
Author(s):  
Jessica Laiman ◽  
Julie Loh ◽  
Wei-Chun Tang ◽  
Mei-Chun Chuang ◽  
Hui-Kang Liu ◽  
...  
Keyword(s):  
Direct Interaction ◽  
Membrane Curvature ◽  
Membrane Dynamics ◽  
Src Homology 3 ◽  
Rich Domain ◽  
Hereditary Myopathy ◽  
Src Homology ◽  
T Tubules ◽  
Endocytic Regulation ◽  
Dynamin 2

Tight regulation of endocytosis ensures accurate control of cellular signaling and membrane dynamics, which are crucial for tissue morphogenesis and functions. Mutations of Bin1 and dynamin-2 (Dyn2), proteins that generate membrane curvature and sever endocytic invaginations, respectively, cause progressive hereditary myopathy. Here, we show that Bin1 inhibits Dyn2 via direct interaction of its SRC Homology 3 (SH3) domain with the proline-rich domain (PRD) of Dyn2. Phosphorylation of S848 of Dyn2 by GSK3α, a kinase downstream of insulin signaling, relieves Dyn2 from the inhibition of Bin1 and promotes endocytosis in muscle. Mutations of Bin1 associated with centronuclear myopathy disrupt its inhibition of Dyn2, thereby exaggerating Dyn2 fission activity and causing excessive fragmentation of T-tubules in the muscle cells. Our work reveals how Bin1-Dyn2 interaction fine-tunes membrane remodeling at the molecular level, and lay the foundation for future exploration of endocytic regulation and hereditary muscle diseases.

Interaction of Grb2 SH3 domain with UVRAG in an Alzheimer’s disease–like scenario

2014 ◽  
Vol 92 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Kasturi Roy ◽  
Oishee Chakrabarti ◽  
Debashis Mukhopadhyay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Sh3 Domain ◽  
Binding Motifs ◽  
Src Homology 3 ◽  
Src Homology ◽  
Cellular Compartmentalization

Growth factor receptor-bound protein 2 (Grb2) is an adaptor protein which participates in trafficking pathways alongside its role in signaling. Proteins important for actin remodeling and cellular compartmentalization contain SRC Homology 3 (SH3) binding motifs that interact with Grb2. While studying the Grb2–amyloid precursor protein (APP) intracellular domain (AICD) interaction in Alzheimer’s disease cell line models, it was seen that Grb2 colocalized to compartments that mature into autophagosomes. The entrapping of AICD in the Grb2 vesicles and its clearance via autophagosomes was a survival contrivance on the part of the cell. Here, we report that Grb2, when in excess, interacts with ultraviolet radiation resistance-associated gene protein (UVRAG) under excess conditions of AICD–Grb2 or Grb2. The N-terminal SH3 domain of Grb2 specifically interacts with UVRAG, unlike the C-terminal SH3 domain. This interaction helps to understand the role of Grb2 in the autophagic maturation of vesicles.

scholarly journals Properties of phagocyte NADPH oxidase p47-phox mutants with unmasked SH3 (Src homology 3) domains: full reconstitution of oxidase activity in a semi-recombinant cell-free system lacking arachidonic acid

2003 ◽  
Vol 373 (1) ◽  
pp. 221-229 ◽  
Author(s):  
Guihong PENG ◽  
Jin HUANG ◽  
Mellonie BOYD ◽  
Michael E. KLEINBERG
Keyword(s):  
Arachidonic Acid ◽  
Nadph Oxidase ◽  
Sh3 Domain ◽  
Free System ◽  
Cell Free System ◽  
Src Homology 3 ◽  
Rich Domain ◽  
Phagocyte Nadph Oxidase ◽  
Px Domain ◽  
Src Homology

In an early step in the assembly of the phagocyte NADPH oxidase, p47-phox translocates from the cytosol to the membrane, mediated by engagement of the N-termini of two p47-phox Src homology 3 (SH3) domains with a proline-rich region (PRR) in the p22-phox subunit of cytochrome b558. In response to phagocyte activation, several serine residues in a C-terminal arginine/lysine-rich domain of p47-phox are phosphorylated, leading to changes in the conformation of p47-phox and exposure of its N-terminal SH3 domain that is normally masked by internal association with the arginine/lysine-rich domain. We report that triple alanine substitutions at Asp-217, Glu-218 and Glu-223 in a short sequence that links the tandem p47-phox SH3 domains unmasked the N-terminal SH3 domain, similar to the effects of aspartic acid substitutions at Ser-310 and Ser-328 in the arginine/lysine-rich region. Recombinant p47-phox proteins with mutations in either the linker region or the arginine/lysine-rich domain were active in the absence of arachidonic acid stimulation in a cell-free NADPH oxidase system consisting of recombinant p67-phox, Rac1–guanosine 5′-[γ-thio]triphosphate and neutrophil membranes. Supplementing neutrophil membranes with phosphoinositides or other negatively charged phospholipids markedly enhanced cell-free superoxide generation by these p47-phox mutants in the absence of arachidonic acid, to levels equivalent to those generated by wild-type p47-phox following arachidonic acid activation. This enhancement may be related to recruitment to the membrane of p47-phox mediated by a novel secondary phox homology (PX) domain binding site that broadly recognizes phospholipids. No specific enhancement by specific phosphorylated phosphatidylinositols was found to suggest a dominant role for the p47-phox primary PX domain binding site. Truncated p47-phox S310D S328D lacking the C-terminal PRR was inactive in the cell-free system without arachidonic acid, but was fully active with arachidonic acid. This suggests that activation of NADPH oxidase in an arachidonate-free cell-free system requires association of the p47-phox C-terminal PRR with the p67-phox C-terminal SH3 domain.

scholarly journals The Role of the Src Homology 3-Src Homology 2 Interface in the Regulation of Src Kinases

2001 ◽  
Vol 276 (20) ◽  
pp. 17199-17205 ◽  
Author(s):  
Stefan T. Arold ◽  
Tobias S. Ulmer ◽  
Terrence D. Mulhern ◽  
Jörn M. Werner ◽  
John E. Ladbury ◽  
...  
Keyword(s):  
Src Kinases ◽  
Src Homology 3 ◽  
Src Homology 2 ◽  
Src Homology

scholarly journals Role of Interfacial Water Molecules in Proline-rich Ligand Recognition by the Src Homology 3 Domain of Abl

2009 ◽  
Vol 285 (4) ◽  
pp. 2823-2833 ◽  
Author(s):  
Andres Palencia ◽  
Ana Camara-Artigas ◽  
M. Teresa Pisabarro ◽  
Jose C. Martinez ◽  
Irene Luque
Keyword(s):  
Ligand Recognition ◽  
Water Molecules ◽  
Interfacial Water ◽  
Src Homology 3 ◽  
Src Homology 3 Domain ◽  
Src Homology

Insights into the structure and protein–protein interactions of the pro-apoptotic protein ASPP2

2007 ◽  
Vol 35 (5) ◽  
pp. 966-969 ◽  
Author(s):  
S. Rotem ◽  
C. Katz ◽  
A. Friedler
Keyword(s):  
Intermolecular Interactions ◽  
Protein Interactions ◽  
Intramolecular Interaction ◽  
Protein Protein Interactions ◽  
Sh3 Domains ◽  
Src Homology 3 ◽  
Rich Domain ◽  
C Terminus ◽  
Apoptotic Protein ◽  
Src Homology

ASPP (apoptosis-stimulating protein of p53) 2 is a pro-apoptotic protein that stimulates the p53-mediated apoptotic response. Here, we provide an overview of the structure and protein–protein interactions of ASPP2. The C-terminus of ASPP2 contains Ank (ankyrin) repeats and an SH3 domain (Src homology 3 domain). The Ank–SH3 domains mediate interactions between ASPP2 and numerous proteins involved in apoptosis such as p53 and Bcl-2. The proline-rich domain of ASPP2 is unfolded in its native state, but was not shown to mediate intermolecular interactions. Instead, it makes an intramolecular domain–domain interaction with the Ank–SH3 C-terminal domains of ASPP2. This intramolecular interaction between the unstructured proline-rich domain and the structured Ank–SH3 domains in ASPP2, which is possible due to the unfolded nature of the proline-rich domain, is proposed to have an important role in regulating the intermolecular interactions of ASPP2 with its partner proteins.

scholarly journals SGIP1α, but Not SGIP1, is an Ortholog of FCHo Proteins and Functions as an Endocytic Regulator

2021 ◽  
Vol 9 ◽  
Author(s):  
Sang-Eun Lee ◽  
Eunji Cho ◽  
Soomin Jeong ◽  
Yejij Song ◽  
Seokjo Kang ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Growth Factor Receptor ◽  
Domain Growth ◽  
Interacting Protein ◽  
Src Homology 3 ◽  
Functional Consequences ◽  
Src Homology 3 Domain ◽  
Src Homology ◽  
Growth Factor Receptor Bound

Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1 (SGIP1), originally known as a regulator of energy homeostasis, was later found to be an ortholog of Fer/Cip4 homology domain-only (FCHo) proteins and to function during endocytosis. SGIP1α is a longer splicing variant in mouse brains that contains additional regions in the membrane phospholipid-binding domain (MP) and C-terminal region, but functional consequences with or without additional regions between SGIP1 and SGIP1α remain elusive. Moreover, many previous studies have either inadvertently used SGIP1 instead of SGIP1α or used the different isoforms with or without additional regions indiscriminately, resulting in further confusion. Here, we report that the additional region in the MP is essential for SGIP1α to deform membrane into tubules and for homo-oligomerization, and SGIP1, which lacks this region, fails to perform these functions. Moreover, only SGIP1α rescued endocytic defects caused by FCHo knock-down. Thus, our results indicate that SGIP1α, but not SGIP1, is the functional ortholog of FCHos, and SGIP1 and SGIP1α are not functionally redundant. These findings suggest that caution should be taken in interpreting the role of SGIP1 in endocytosis.

scholarly journals Role of the Basic, Proline-rich Region of Dynamin in Src Homology 3 Domain Binding and Endocytosis

1997 ◽  
Vol 272 (17) ◽  
pp. 11629-11635 ◽  
Author(s):  
Patricia M. Okamoto ◽  
Jonathan S. Herskovits ◽  
Richard B. Vallee
Keyword(s):  
Rich Region ◽  
Src Homology 3 ◽  
Src Homology 3 Domain ◽  
Src Homology ◽  
Proline Rich Region

scholarly journals Cortactin Has an Essential and Specific Role in Osteoclast Actin Assembly

2006 ◽  
Vol 17 (7) ◽  
pp. 2882-2895 ◽  
Author(s):  
Shandiz Tehrani ◽  
Roberta Faccio ◽  
Indra Chandrasekar ◽  
F. Patrick Ross ◽  
John A. Cooper
Keyword(s):  
Actin Assembly ◽  
Wild Type ◽  
Tyrosine Residues ◽  
Src Homology 3 ◽  
No Formation ◽  
Sealing Ring ◽  
Src Homology ◽  
Bone Dynamics

Osteoclasts are essential for bone dynamics and calcium homeostasis. The cells form a tight seal on the bone surface, onto which they secrete acid and proteases to resorb bone. The seal is associated with a ring of actin filaments. Cortactin, a c-Src substrate known to promote Arp2/3-mediated actin assembly in vitro, is expressed in osteoclasts and localizes to the sealing ring. To address the role of cortactin and actin assembly in osteoclasts, we depleted cortactin by RNA interference. Cortactin-depleted osteoclasts displayed a complete loss of bone resorption with no formation of sealing zones. On nonosteoid surfaces, osteoclasts flatten with a dynamic, actin-rich peripheral edge that contains podosomes, filopodia, and lamellipodia. Cortactin depletion led to a specific loss of podosomes, revealing a tight spatial compartmentalization of actin assembly. Podosome formation was restored in cortactin-depleted cells by expression of wild-type cortactin or a Src homology 3 point mutant of cortactin. In contrast, expression of a cortactin mutant lacking tyrosine residues phosphorylated by Src did not restore podosome formation. Cortactin was found to be an early component of the nascent podosome belt, along with dynamin, supporting a role for cortactin in actin assembly.

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