Austr

alia
Assig
nmen
t
Joseph
Addison

[MECHANISM
ASSIGNMENT]
There is no evidence of presence of FGF genes in the unicellular organisms,
Saccharomyces cerevisiae).

Introduction
Based on the way of mechanism of FGF actions, we can classify FGF activities
into three types: intracrine, paracrine, and endocrine.
FGF Paraclete subfamilies include FGF1, FGF2, 3, 7, 10 and 22, FGF22, 4, 5, 6, 8,
17, 9, 16, 20 etc. Almost all the FGF family members possess an N terminal
secretory signal pep tide which is cleanable and for exporting through the ER and
Golgi apparatus pathway. Though, there is no presence of secretory signal
peptide in FGF 1 and 2 and are represented to be shown as exporting from the
cells by the independent method of conventional ER Golgi apparatus pathway.
A classical secretory pathway is shared by the subfamily FGF9 members, but they
dont possess a cleavable signal sequence. Rather, they have a secretory signal
sequence which is bipartite in nature to interact with the secretory machinery. All
the FGF paracrine bind themselves with HS strongly and a glycosaminoglycan in
the pericellular and the extracellular matric, binds them at binding sites of
heparin. Thus as result of this interaction, their diffusion radius limits so much
that all the FGFs start exerting biological impacts surrounding the synthesis
source.
FGF intracrine are FGF 11 subfamily members which are found as intracellular
protiens in the cells. FGFs intracrine are said to play an important role in the
excitability regulation of the granular neurons. The members of FGF19 dont bind
to HS or if they do it very weak, hence they function in the endocrine
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HS is bound by only FGF paracrine. There are several experimental systems
which shows the FGF transport is controlled by HS. For eg, the mutations in SGL
(gene coding sugarless) and SFL 9Sulfateless,which are often found to be
indispent in the heparin sulfate chain biosynthesis, were recognized to be
showing phenotyope to WG (Wingless) or Hh (Hedgehog) signalling the
mutants.The FGF diffusion is regulated by the HS interaction taking place in the

extracellular matrix, thus the form of concentration gradients of FGF is

determined, along with the FGF release and storage.The GF (growth factor)/
morphogen type signals which FGF generates, need the assembly of the FGF
ternary ligand complex, HS and FGFR (receptor) by which both receptors and
ligands are engaged. Hence, HS works as the co receptor.Read more
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Evolution of the FGF Gene Family

There is no evidence of presence of FGF genes in the unicellular organisms
( E. coli, Saccharomyces cerevisiae). Two (egl 17 and let 756) and three FGF
genes ( branch less, pyramus and thisbe) were found and identified after
performing the genome sequencing Drosophila and Caenorhabditis elegans.
Later, based on genome sequencing, there were six more genes found and
identified in ascidian Ciona intestinalis, a basal chordate, these are said to be the
ancestral genes of FGF subfamilies of human genes, including FGF 4 like, FGF
5 like, FGF 8 like, FGF 9 like, FGF 10 likes and FGF 13 like.
In mouse, human and zebra fish FGF families, so far there have been total 22
FGF genes identified. The FGF gene subfamilies ancestral genes resulted in the
gene duplication based on a hypothesis which followed the deuterostomes and
protostomes divergence. An evolution history model is proposed which presents
the two phases of gene expansion. The first phase explains gene duplication
which took place due to the FGFgene results from two or more than two genes (3
to 6 genes) during the process of early metalanguage evolution. Second phase
explains two large scale genome duplications from which full complement of
vertebrate genes were generated.

Possible Evolutionary relationships between FGF Geens

The ancestral gene inthe entire FGF family is FGF 13 like gene. Gene
duplication generated the FGF 4- like gene at a very early stage from the FGF 13
like. The gene duplication generated FGF 5 like, FGF 8 like, FGF 9 like,
FGF 10 like and FGF 15/19 like in first phase. The second phase resulted in
the expansion of all FGFs and became three to four members.

STRUCTURE MOLECULE INFO ON: FGFS THEN FGFRS

FGFs: Their molecular weight ranges from scale of 17 to 34 KDa in case of
vertebrates while Drosophila has a molecular weight of 84 KDa. There is a similar
structural core shared by all of the FGFs with 28 being very conserved, with
residues of amino acids with 6 invariants. The X Ray Crystallography done on
FGFs presented a very similar pattern of folding the interleukins IL ! and IL1.

HS: There are repeated units of disaccharides which are joined together by a 1 4
linkage bong. The synthesized chains of HS always bind to the core protein for
forming the HSPGs (Heparan Sulfate Proteoglyans). HSPG is a core protein
which regulates the synthesized chains of HS to bind to their functional sites,
including extracellular matrix or cell surface. Heparin is most commonly
experimented as an HS proxy,is a more sulfated structure nevertheless.Read
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FGFRs: These are described as immunoglobulin domains i.e. I, II,and III. On the
domain I location, the heparin binding location is stained orange. There is a black
box which is acid box in between the domain II and domain III. FGF interacts
and attaches to the Ig II and FGF ligands bind with the Ig III adjacent surfaces.
The portion which is green colored is the second half of spliced immunoglobulin
domains III. (TK: tyrosine kinase).

FGFR Domain Structure

Endosomal Escape

Nanoparticles are transported within the vesicles cells by endocytosis, which

depends on the internalization mode. Are either recycled or trafficked back to the
cell organelles, which include the golgi mitochondria, golgi and thelysosomes. A
complex process of intracellular transport, endosomal trafficking transport
protiens within the cells. This process shortens the vesicles and these are
dissociated or fused, along with the lysosomes and endosomes.
For the nanoparticles which target he endolysosomal network, like those which
are used to treat the lysosomalstorage disorder, the targets are provided with
rapid access by endocytic uptake. Though in case of application,the nanoparticles
are trapped within the vesicle is always undesirable.Further more, the vesicles
mature into the lysosomes and endosomes, which is presented with help iof
immediate acidification from the pH scale value of 6 to 4, inside the vesciles and
degradative enzymes are employed to digest the content of these vesciles.
Nanoparticles are required to be equipped with the methods and mechanisms so
that they can escape from the network of endolysome.
Fig 3: Intracellular transport of nanoparticles: Once the internalization is done
with help of any of endocytic pathways, these nanoparticles are transported to the
endolysomal network using cytoskeletal structures and motor protiens. The
vesicle content can be transported to the sortingendosommes, or they can be
recycled back to the cell surface suing the plasma membrane fusion process. On
the other side, the maturation of endosomes can take place to lysosomes using a
luminal acidication using the degradative enzymes so that the degradative vesicle
content can be targeted. For accessing the nuclear targets or the cytoplasmic
targets, the nanoparticles should be able to escape from the network of
endosomes and also be able to traverse back to the crowded cytoplasm.