science

Phosphatidylinositol 3,5-bisphosphate

Phosphatidylinositol 3,5-bisphosphate is a science topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Phosphatidylinositol 3,5-bisphosphate rather than just read about it. In short: Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) is one of the seven phosphoinositides found in eukaryotic cell membranes. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides.

Key takeaways

Phosphatidylinositol 3,5-bisphosphate belongs to science; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Phosphatidylinositol 3,5-bisphosphate to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Phosphatidylinositol 3,5-bisphosphate from memory before moving on to harder problems.

Reference excerpt

Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) is one of the seven phosphoinositides found in eukaryotic cell membranes. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides. They are approximately 3 to 5-fold lower as compared to PtdIns3P and PtdIns5P (Phosphatidylinositol 5-phosphate) levels, and more than 100-fold lower than the abundant PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2. PtdIns(3,5)P2 was first reported to occur in mouse fibroblasts and budding yeast S. cerevisiae in 1997. In S. cerevisiae PtdIns(3,5)P2 levels increase dramatically during hyperosmotic shock. The response to hyperosmotic challenge is not conserved in most tested mammalian cells except for differentiated 3T3L1 adipocytes.

Metabolism The only currently known pathway for PtdIns(3,5)P2 production is through synthesis catalyzed by the phosphoinositide kinase PIKfyve. Pulse-chase experiments in mouse fibroblasts reveal that PtdIns(3,5)P2 is reverted to PtdIns3P soon after its synthesis. In mammalian cells, PtdIns(3,5)P2 is synthesized from and turned over to PtdIns3P by a unique protein complex containing two enzymes with opposite activities: the phosphoinositide kinase PIKfyve and the Sac1 domain-containing PtdIns(3,5)P2 5-phosphatase, Sac3/Fig4. The two enzymes do not interact directly. Rather, they are brought together by an associated regulator of PIKfyve, called ArPIKfyve/VAC14, that scaffolds a ternary regulatory complex, known as the PAS complex (from the first letters of PIKfyve/ArPIKfyve/Sac3). PIKfyve attaches the PAS complex onto Rab5GTP/PtdIns3P-enriched endosomal microdomains via its FYVE finger domain that selectively binds PtdIns3P.

The essential role of the PAS complex in PtdIns(3,5)P2 synthesis and turnover is supported by data from siRNA-mediated protein silencing and heterologous expression of the PAS complex components in various cell types as well as by data from genetic knockout of the PAS complex proteins.

An additional pathway for PtdIns(3,5)P2 turnover involves the myotubularin family of phosphatases. Myotubularin 1 and MTMR2 dephosphorylate the 3-position of PtdIns(3,5)P2; therefore, the product of this hydrolysis is PtdIns5P, rather than PtdIns3P.

The PAS complex proteins are evolutionarily conserved with orthologs found in S. cerevisiae (i.e., Fab1p, Vac14p, and Fig4p proteins) as well as in all eukaryotes with sequenced genomes. Therefore, it is believed that PtdIns(3,5)P2 is present in all eukaryotes where it regulates similar cellular functions. Yeast Fab1p, Vac14p, and Fig4p also form a complex, called the Fab1 complex.

However, the Fab1 complex contains additional proteins,

which might add an additional layer of PtdIns(3,5)P2 regulation in yeast. The composition of the protein complexes regulating PtdIns(3,5)P2 levels in other species is yet to be clarified.

Functions and regulation PtdIns(3,5)P2 regulates endosomal operations (fission and fusion) that maintain endomembrane homeostasis and proper performance of the trafficking pathways emanating from or traversing endosomes. Decrease of PtdIns(3,5)P2 levels upon perturbations of cellular PIKfyve by heterologous expression of enzymatically inactive PIKfyve point mutants,

siRNA-medicated silencing,

pharmacological inhibition

and PIKFYVE knockout

all cause formation of multiple cytosolic vacuoles, which become larger over time. Importantly, the vacuolation induced by PIKfyve dysfunction and PtdIns(3,5)P2 depletion is reversible and could be selectively rescued by cytosolic microinjection of PtdIns(3,5)P2,

overexpression of PIKfyve

or wash-out of the PIKfyve inhibitor YM201636.

Sac3 phosphatase activity in the PAS complex also plays an important role in regulating PtdIns(3,5)P2 levels and maintaining endomembrane homeostasis. Thus, cytoplasmic vacuolation induced by the dominant-negative PIKfyveK1831E mutant is suppressed upon co-expression of a Sac3 phosphatase-inactive point-mutant along with ArPIKfyve.

In vitro reconstitution assays of endosome fusion and multivesicular body (MVB) formation/detachment (fission) suggest a positive role of PtdIns(3,5)P2 in MVB fission from maturing early endosomes and a negative role in endosome fusion.

PtdIns(3,5)P2 is implicated in the microtubule-dependent retrograde transport from early/late endosomes to the trans Golgi network.

Acute insulin treatment increases PtdIns(3,5)P2 levels in 3T3L1 adipocytes, both in isolated membranes and intact cells to promote insulin effect on GLUT4 cell surface translocation and glucose transport.

These cells also show a marked PtdIns(3,5)P2 increase upon hyperosmotic shock.

Other stimuli, including mitogenic signals such as IL-2 and UV light in lymphocytes,

activation of protein kinase C by PMA in platelets

and EGF stimulation of COS cells,

also increase PtdIns(3,5)P2 levels. PtdIns(3,5)P2 plays a key role in growth and development as evidenced by the preimplantation lethality of the PIKfyve knockout mouse model. The fact that the heterozygous PIKfyve mice are ostensibly normal and live to late adulthood with only ~60% of the wild-type PtdIns(3,5)P2 levels suggests that PtdIns(3,5)P2 might normally be in excess.

ArPIKfyve/Vac14 or Sac3/Fig4 knockout in mice results in a 30-50% decrease in PtdIns(3,5)P2 levels and cause similar massive central neurodegeneration and peripheral neuropathy.

These studies suggest that reduced PtdIns(3,5)P2 levels, by a yet-to-be identified mechanism, mediate neuronal death. In contrast, MTMR2 phosphatase knockout, which also causes peripheral neuropathy, is accompanied by elevation in PtdIns(3,5)P2.

Thus, whether and how the abnormal levels of PtdIns(3,5)P2 selectively affect peripheral neuronal functions remains unclear.

Effectors Phosphoinositides are generally viewed as membrane-anchored signals recruiting specific cytosolic effector proteins. So far, several proteins have been proposed as potential PtdIns(3,5)P2 effectors. Unfortunately, the expectations that such effectors would be evolutionary conserved and share a common PtdIns(3,5)P2-binding motif of high affinity remain unfulfilled. For example, deletion of Atg18p, a protein involved also in autophagy in S. cerevisiae, causes enlarged vacuole and 10-fold elevation in PtdIns(3,5)P2. Atg18p binds PtdIns(3,5)P2 with high affinity and specificity.

However, except for autophagy, the mammalian orthologs of Atg18p do not share similar functions.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with Phosphatidylinositol 3,5-bisphosphate

Start with the simplest possible case. Write down what Phosphatidylinositol 3,5-bisphosphate claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In science, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Phosphatidylinositol 3,5-bisphosphate before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Phosphatidylinositol 3,5-bisphosphate ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Phosphatidylinositol 3,5-bisphosphate

In research: Phosphatidylinositol 3,5-bisphosphate appears in science research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Phosphatidylinositol 3,5-bisphosphate in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Phosphatidylinositol 3,5-bisphosphate is common in secondary-school and first-year university syllabi. It links to neighbouring topics Phospholipids, so understanding it makes those chapters shorter.
In everyday life: Look for Phosphatidylinositol 3,5-bisphosphate outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study Phosphatidylinositol 3,5-bisphosphate in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Phosphatidylinositol 3,5-bisphosphate means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Phosphatidylinositol 3,5-bisphosphate out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Phosphatidylinositol 3,5-bisphosphate in simple terms?

Why does Phosphatidylinositol 3,5-bisphosphate matter?

Because it connects several science ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Phosphatidylinositol 3,5-bisphosphate?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Phosphatidylinositol 3,5-bisphosphate.