The hairpin stack fold, a novel protein architecture for a new family of protein growth factors

Hrabal, Richard; Chen, Zhigang; James, Susan; Bennett, H. P. J.; Ni, Feng

doi:10.1038/nsb0996-747

Cited by 166 publications

(178 citation statements)

References 27 publications

Supporting

Mentioning

172

Contrasting

Unclassified

Order By: Relevance

“…Two-dimensional nuclear magnetic resonance analysis of purified carp GRN-1 revealed that the peptide backbone adopts a unique conformation of a parallel stack of beta-hairpins in the form of a left-handed helix. (3) Recombinant mammalian GRN modules show a similar, but less rigid structure (4) (Fig. 1B).…”

Section: Introductionmentioning

confidence: 98%

The granulin gene family: from cancer to dementia

2009

View full text Add to dashboard Cite

The growth factor progranulin (PGRN) regulates cell division, survival, and migration. PGRN is an extracellular glycoprotein bearing multiple copies of the cysteine-rich granulin motif. With PGRN family members in plants and slime mold, it represents one of the most ancient of the extracellular regulatory proteins still extant in modern animals. PRGN has multiple biological roles. It contributes to the regulation of early embryogenesis, to adult tissue repair and inflammation. Elevated PGRN levels often occur in cancers, and PGRN immunotherapy inhibits the growth of hepatic cancer xenografts in mice. Recent studies have demonstrated roles for PGRN in neurobiology. An autosomal dominant mutation in GRN, the gene for PGRN, leads to neuronal atrophy in the frontal and temporal lobes, resulting in the disease frontotemporal lobar dementia. In this review we will discuss current knowledge of the multifaceted biology of PGRN.

show abstract

Section: Introductionmentioning

confidence: 98%

The granulin gene family: from cancer to dementia

2009

View full text Add to dashboard Cite

show abstract

“…GrnA to F contain 12 highly conserved cysteine (Cys) residues (Fig. 1) Plowman et al, 1992] and are folded in four stacked b-hairpins twisted around an axial rod of disulfide bridges [Hrabal et al, 1996]. GrnG contains only 10 Cys residues Plowman et al, 1992] but it was suggested that the lack of two Cys residues remains compatible with a stacked b-hairpin fold [Hrabal et al, 1996].…”

Section: Grn Protein and Genementioning

confidence: 99%

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

2008

View full text Add to dashboard Cite

Communicated by Mark H. PaalmanMutations in the gene encoding granulin (HUGO gene symbol GRN, also referred to as progranulin, PGRN), located at chromosome 17q21, were recently linked to tau-negative ubiquitin-positive frontotemporal lobar degeneration (FTLDU). Since then, 63 heterozygous mutations were identified in 163 families worldwide, all leading to loss of functional GRN, implicating a haploinsufficiency mechanism. Together, these mutations explained 5 to 10% of FTLD. The high mutation frequency, however, might still be an underestimation because not all patient samples were examined for all types of loss-of-function mutations and because several variants, including missense mutations, have a yet uncertain pathogenic significance. Although the complete phenotypic spectrum associated with GRN mutations is not yet fully characterized, it was shown that it is highly heterogeneous, suggesting the influence of modifying factors. A role of GRN in neuronal survival was suggested but the exact mechanism by which neurodegeneration and deposition of pathologic brain inclusions occur still has to be clarified. Hum Mutat 29(12), [1373][1374][1375][1376][1377][1378][1379][1380][1381][1382][1383][1384][1385][1386] 2008.

show abstract

“…The larger precursor is known by several names, including granulin/epithelin precursor (8), proepithelin (9), acrogranin (10), PC cell-derived growth factor (PCDGF) (11), and progranulin. Granulins have a unique 12-cysteine motif that is arranged in four ␤-hairpins, stacked one upon another in a helical formation and connected via a central rod of disulfide bonds (12)(13)(14). Structurally, granulins are distinct from most growth factors, with the exception of the epidermal growth factor/transforming growth factor-␣ family (13).…”

mentioning

confidence: 99%

“…Granulins have a unique 12-cysteine motif that is arranged in four ␤-hairpins, stacked one upon another in a helical formation and connected via a central rod of disulfide bonds (12)(13)(14). Structurally, granulins are distinct from most growth factors, with the exception of the epidermal growth factor/transforming growth factor-␣ family (13). In addition to the mammalian granulins of human (1,6), rat (2,12), mouse (10,15), and horse (16), granulin-like proteins have been identified in a number of non-mammalian organisms including the nematode Caenorhabditis elegans (17), the locust (18), the mussel (19), the marine worm Hediste diversicolor (20), and teleosts (bony fish) (21)(22)(23).…”

mentioning

confidence: 99%

A Novel Hematopoietic Granulin Induces Proliferation of Goldfish (Carassius auratus L.) Macrophages

Hanington

Barreda

Belosevic

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Granulins are a group of highly conserved growth factors that have been described from a variety of organisms spanning the metazoa. In this study, goldfish granulin was one of the most commonly identified transcripts in the differential cross-screening of macrophage cDNA libraries and was preferentially expressed in proliferating macrophages. Unlike mammalian granulins, which possess 7.5 repeats of a characteristic signature of 12 cysteine residues, the goldfish granulin encoded a putative peptide possessing only 1.5 cysteine repeats. Northern blot and real-time PCR analyses indicated that goldfish granulin was expressed only in the hematopoietic tissues of the goldfish, specifically the kidney and spleen, and in activated peripheral blood mononuclear cells. We expressed granulin using a prokaryotic expression system and produced an affinitypurified rabbit anti-goldfish granulin IgG. Recombinant goldfish granulin induced a dose-dependent proliferative response of goldfish macrophages that was inversely related to the myeloid differentiation stage of the cells studied. The highest proliferative response was observed in macrophage progenitor cells and monocytes. This proliferative response of macrophages was abrogated by the addition of anti-granulin IgG. These results indicate that goldfish granulin is a growth factor that positively modulates cell proliferation at distinct junctures of macrophage differentiation.

show abstract

The hairpin stack fold, a novel protein architecture for a new family of protein growth factors

Abstract: The granulin/epithelin protein motif has an unusual structure consisting of a parallel stack of beta-hairpins stapled together by six disulphide bonds. The new structure also contains a folding subdomain shared by small toxins, protease inhibitors as well as the EGF-like protein modules.

Cited by 166 publications

References 27 publications

The granulin gene family: from cancer to dementia

The granulin gene family: from cancer to dementia

Granulin mutations associated with frontotemporal lobar degeneration and related disorders: An update

A Novel Hematopoietic Granulin Induces Proliferation of Goldfish (Carassius auratus L.) Macrophages

Contact Info

Product

Resources

About