Ubiquitin-Binding Proteins: Decoders of Ubiquitin-Mediated Cellular Functions

Abstract The IGF2 mRNA-binding protein family (IGF2BPs) directs the cytoplasmic fate of various target mRNAs and controls essential cellular functions. The three IGF2BP paralogues expressed in mammals comprise two RNA-recognition motifs (RRM) as well as four KH domains. How these domains direct IGF2BP paralogue-dependent protein function remains largely elusive. In this study, we analyze the role of KH domains in IGF2BPs by the mutational GXXG-GEEG conversion of single KH domain loops in the context of full-length polypeptides. These analyses reveal that all four KH domains of IGF2BP1 and IGF2BP2 are essentially involved in RNA-binding in vitro and the cellular association with RNA-binding proteins (RBPs). Moreover the KH domains prevent the nuclear accumulation of these two paralogues and facilitate their recruitment to stress granules. The role of KH domains appears less pronounced in IGF2BP3, because GxxG-GEEG conversion in all four KH domains only modestly affects RNA-binding, subcellular localization and RNA-dependent protein association of this paralogue. These findings indicate paralogue-dependent RNA-binding properties of IGF2BPs which likely direct distinct cellular functions. Our findings suggest that IGF2BPs contact target RNAs via all four KH domains. This implies significant structural constraints, which presumably allow the formation of exceedingly stable protein-RNA complexes.

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Ubiquilins in the crosstalk among proteolytic pathways

Biological Chemistry ◽

10.1515/hsz-2012-0120 ◽

2012 ◽

Vol 393 (6) ◽

pp. 441-447 ◽

Cited By ~ 31

Author(s):

Dong Yun Lee ◽

Eric J. Brown

Keyword(s):

Protein Degradation ◽

Binding Proteins ◽

Major Protein ◽

Degradation Pathways ◽

Cytosolic Proteins ◽

Sequestosome 1 ◽

Ubiquitin Binding ◽

Proteolytic Pathways

Abstract Protein degradation occurs through several distinct proteolytic pathways for membrane and cytosolic proteins. There is evidence that these processes are linked and that crosstalk among these major protein degradation pathways occurs. Ubiquilins, a family of ubiquitin-binding proteins, are involved in all protein degradation pathways. This minireview provides an overview of ubiquilin function in protein degradation and contrasts it with sequestosome-1 (p62), a protein that also has been implicated in multiple proteolytic pathways.

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Targeting heparin and heparan sulfate protein interactions

Organic & Biomolecular Chemistry ◽

10.1039/c7ob01058c ◽

2017 ◽

Vol 15 (27) ◽

pp. 5656-5668 ◽

Cited By ~ 44

Author(s):

Ryan J. Weiss ◽

Jeffrey D. Esko ◽

Yitzhak Tor

Keyword(s):

Extracellular Matrix ◽

Cell Surface ◽

Heparan Sulfate ◽

Protein Interactions ◽

Human Disease ◽

Binding Proteins ◽

Cellular Functions ◽

Animal Cells ◽

Carbohydrate Chains

Heparan sulfate is ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These negatively-charged carbohydrate chains play essential roles in many important cellular functions by interacting with various heparan sulfate binding proteins (HSBP). This review discusses methods for targeting these complex biomolecules, as strategies for treating human disease.

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Actin Binding Proteins: Regulation of Cytoskeletal Microfilaments

Physiological Reviews ◽

10.1152/physrev.00026.2002 ◽

2003 ◽

Vol 83 (2) ◽

pp. 433-473 ◽

Cited By ~ 621

Author(s):

C. G. Dos Remedios ◽

D. Chhabra ◽

M. Kekic ◽

I. V. Dedova ◽

M. Tsubakihara ◽

...

Keyword(s):

Actin Filaments ◽

Binding Proteins ◽

Complex Structure ◽

Actin Binding ◽

Cellular Functions ◽

Actin Binding Proteins ◽

Ancestral Gene ◽

Wide Range ◽

Human Disorders ◽

And Function

The actin cytoskeleton is a complex structure that performs a wide range of cellular functions. In 2001, significant advances were made to our understanding of the structure and function of actin monomers. Many of these are likely to help us understand and distinguish between the structural models of actin microfilaments. In particular, 1) the structure of actin was resolved from crystals in the absence of cocrystallized actin binding proteins (ABPs), 2) the prokaryotic ancestral gene of actin was crystallized and its function as a bacterial cytoskeleton was revealed, and 3) the structure of the Arp2/3 complex was described for the first time. In this review we selected several ABPs (ADF/cofilin, profilin, gelsolin, thymosin β4, DNase I, CapZ, tropomodulin, and Arp2/3) that regulate actin-driven assembly, i.e., movement that is independent of motor proteins. They were chosen because 1) they represent a family of related proteins, 2) they are widely distributed in nature, 3) an atomic structure (or at least a plausible model) is available for each of them, and 4) each is expressed in significant quantities in cells. These ABPs perform the following cellular functions: 1) they maintain the population of unassembled but assembly-ready actin monomers (profilin), 2) they regulate the state of polymerization of filaments (ADF/cofilin, profilin), 3) they bind to and block the growing ends of actin filaments (gelsolin), 4) they nucleate actin assembly (gelsolin, Arp2/3, cofilin), 5) they sever actin filaments (gelsolin, ADF/cofilin), 6) they bind to the sides of actin filaments (gelsolin, Arp2/3), and 7) they cross-link actin filaments (Arp2/3). Some of these ABPs are essential, whereas others may form regulatory ternary complexes. Some play crucial roles in human disorders, and for all of them, there are good reasons why investigations into their structures and functions should continue.

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Regulation of ubiquitin-binding proteins by monoubiquitination

Nature Cell Biology ◽

10.1038/ncb1354 ◽

2006 ◽

Vol 8 (2) ◽

pp. 163-169 ◽

Cited By ~ 226

Author(s):

Daniela Hoeller ◽

Nicola Crosetto ◽

Blagoy Blagoev ◽

Camilla Raiborg ◽

Ritva Tikkanen ◽

...

Keyword(s):

Binding Proteins ◽

Ubiquitin Binding

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It's all about talking: two-way communication between proteasomal and lysosomal degradation pathways via ubiquitin

AJP Cell Physiology ◽

10.1152/ajpcell.00074.2016 ◽

2016 ◽

Vol 311 (2) ◽

pp. C166-C178 ◽

Cited By ~ 20

Author(s):

Martina P. Liebl ◽

Thorsten Hoppe

Keyword(s):

Binding Proteins ◽

Covalent Attachment ◽

Special Importance ◽

Heat Shock Factors ◽

Substrate Selection ◽

E3 Ligases ◽

Age Related ◽

General Decline ◽

Ubiquitin Binding ◽

Proteolytic Pathways

Selective degradation of proteins requires a fine-tuned coordination of the two major proteolytic pathways, the ubiquitin-proteasome system (UPS) and autophagy. Substrate selection and proteolytic activity are defined by a plethora of regulatory cofactors influencing each other. Both proteolytic pathways are initiated by ubiquitylation to mark substrate proteins for degradation, although the size and/or topology of the modification are different. In this context E3 ubiquitin ligases, ensuring the covalent attachment of activated ubiquitin to the substrate, are of special importance. The regulation of E3 ligase activity, competition between different E3 ligases for binding E2 conjugation enzymes and substrates, as well as their interplay with deubiquitylating enzymes (DUBs) represent key events in the cross talk between the UPS and autophagy. The coordination between both degradation routes is further influenced by heat shock factors and ubiquitin-binding proteins (UBPs) such as p97, p62, or optineurin. Mutations in enzymes and ubiquitin-binding proteins or a general decline of both proteolytic systems during aging result in accumulation of damaged and aggregated proteins. Thus further mechanistic understanding of how UPS and autophagy communicate might allow therapeutic intervention especially against age-related diseases.

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