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1. Structure
2. Cancer
3. Wounds
4. Brain

Progranulin and Granulin/Epithelin Modules † 

Progranulin is a secreted, cysteine-rich glycoprotein that regulates cell division, survival, motility and migration. It has roles in development, wound repair, and cancer. Mutations in a single copy of the progranulin gene cause a form of early onset dementia (frontotemporal dementia).

Chapter 1: Protein and Gene Structure:

Several names are used, thus (in alphabetic order) acrogranin, epithelin-precursor, granulin-epithelin precursor (GEP), PC-derived cell growth factor, proepithelin and progranulin all refer to the same molecule. In humans this consists of seven and a half repeats of a common 12-cysteine module called granulin /epithelin module (GEM). The number of GEMs per human progranulin is 7½ but this varies through evolution with up to 12½ in the African clawed toad (Xenopus) and 1 in Lumbricus rubellus (an earthworm). GEMs are well conserved between species, the linker sequences are less conserved.

Each granulin/epithelin module (GEM) consists of 12 cysteines connected in 6 disulfide bridges.

xCxDxxxxCPDxxTCCxxxxGxxGCCPxxxxxCCxDxxHCCPxxxxCDxxxCC
(C= half cystine; D =aspartic acid; P = proline; T =Threonine; G = glycine; H= histidine)

A similar motif (with a slight variation) is found at the C-terminus of many plant thiol proteases.

There are 12 protein coding exons and a further 5'non-coding exon. Each GEM is encoded by 2 exons. Coding Exons 1- 8 and 12 encode either the N- or C-terminal half of a single GEM; Exons 9-11 encode the C-terminus of a GEM and the N-terminus of the adjacent GEM (CN).

The exon pattern for human progranulin is therefore:

NNCNCNCN—[CN]—[CN]—[CN]—C
granulin gene structure
model of granulin domain
Spatial conformation of a granulin unit
  • The position of exon-intron boundaries are highly conserved through evolution.
  • Alternate splicing has been reported.
  • Intact progranulin is glycosylated.

The 3-dimensional structure of granulin from carp is shown. There are four beta-hairpins (blue ribbons) stacked one above the other in a twisted ladder-like formation. Six disulfide bridges (yellow balls) pass through the centre of the molecule.

The 3-D structure is unique to granulin/epithelin but can be partially superimposed on the 3-dimensional fold of epidermal growth factor.

Chapter 2: Progranulin in cancer —>

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 †  Queries and comments on the material in these chapters should be addressed to Andrew Bateman

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