Interaction Codes within the Family of Mammalian Phox and Bem1p Domain-containing Proteins

Lamark, Trond; Perander, Maria; Outzen, Heidi; Kristiansen, Kurt; Øvervatn, Aud; Michaelsen, Espen; Bjørkøy, Geir; Johansen, Terje

doi:10.1074/jbc.m303221200

Cited by 347 publications

(416 citation statements)

References 51 publications

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“…The PB1 domain has been shown previously to self-associate (forming homo-oligomers) in yeast two-hybrid studies. 37 Consistent with a previous structural characterization of TFG, 38 we found that the wild-type PB1 domain, at concentrations ranging from 18-45 μM, formed octamers in solution (~92 kD). In contrast, the c.64C4T (p. (Arg22Trp)) mutant of the PB1 domain exhibited a significantly reduced molecular mass of~24 kD (around one-fourth of the wild-type protein mass) throughout the same range of protein concentrations, indicating it was only capable of forming dimers rather than octamers.…”

Section: Biochemical Impact Of the Novel Tfg C64c4t Variantsupporting

confidence: 91%

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

et al. 2016

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Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSPrelated genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C4T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C4T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

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Section: Biochemical Impact Of the Novel Tfg C64c4t Variantsupporting

confidence: 91%

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

et al. 2016

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“…The N-terminal Phox and Bem1 (PB1) domain (aa 20-102) is necessary for p62/SQSTM1 to oligomerize and to interact with other PB1-containing proteins (Lamark et al 2003). Through the PB1 domain, p62/ SQSTM1 associates with several kinases, like atypical protein kinase C (aPKC) and p56 lck , and participates in signal transduction cascades (Joung et al 1996;Sanchez et al 1998).…”

Section: Structurementioning

confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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“…p62 homo-oligomerizes through the self-interaction of its PB1 domain (Lamark et al, 2003;Wilson et al, 2003). Although NBR1 also possesses a PB1 domain (through which it interacts with p62), it instead forms homo-oligomers via its coiled-coil domain (CC1) .…”

Section: P62 Increases the Efficiency Of Nbr1-mediated Pexophagymentioning

confidence: 99%

NBR1 acts as an autophagy receptor for peroxisomes

Deosaran

Larsen

Hua

et al. 2012

Journal of Cell Science

Self Cite

290

359

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SummarySelective macro-autophagy is an intracellular process by which large cytoplasmic materials are selectively sequestered and degraded in the lysosomes. Substrate selection is mediated by ubiquitylation and recruitment of ubiquitin-binding autophagic receptors such as p62, NBR1, NDP52 and Optineurin. Although it has been shown that these receptors act cooperatively to target some types of substrates to nascent autophagosomes, their precise roles are not well understood. We examined selective autophagic degradation of peroxisomes (pexophagy), and found that NBR1 is necessary and sufficient for pexophagy. Mutagenesis studies of NBR1 showed that the amphipathic a-helical J domain, the ubiquitin-associated (UBA) domain, the LC3-interacting region and the coiled-coil domain are necessary to mediate pexophagy. Strikingly, substrate selectivity is partly achieved by NBR1 itself by coincident binding of the J and UBA domains to peroxisomes. Although p62 is not required when NBR1 is in excess, its binding to NBR1 increases the efficiency of NBR1-mediated pexophagy. Together, these results suggest that NBR1 is the specific autophagy receptor for pexophagy.

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Interaction Codes within the Family of Mammalian Phox and Bem1p Domain-containing Proteins

Cited by 347 publications

References 51 publications

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan

p62/SQSTM1 at the interface of aging, autophagy, and disease

NBR1 acts as an autophagy receptor for peroxisomes

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